HIV protease inhibitors, compositions containing the same, their pharmaceutical uses and materials for their synthesis

ABSTRACT

Compounds of the formula:  
                 
where the formula variables are as defined herein, are disclosed that advantageously inhibit or block the biological activity of the HIV protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with the HIV virus. Intermediates and synthetic methods for preparing such compounds are also described.

This application is a continuation of U.S. patent application Ser. No.10/166,979, filed Jun. 11, 2002, which claims the benefit of U.S.Provisional Application No. 60/297,460, filed on Jun. 11, 2001, and U.S.Provisional Application 60/297,729, filed on Jun. 11, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel compounds useful as HIV proteaseinhibitors and to the use of such compounds as antiviral agents fortreatment of HIV infected individuals. This invention also relates tomethods of preparation of these compounds and to intermediates that areuseful in the preparation thereof.

2. Related Background Art

Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown ofthe body's immune system as well as progressive deterioration of thecentral and peripheral nervous systems. Since its initial recognition inthe early 1980's, AIDS has spread rapidly and has now reachedepidemic-proportions within a relatively limited segment of thepopulation. Intensive research has led to the discovery of theresponsible agent, human T-lymphotropic retrovirus III (HTLV-III), nowmore commonly referred to as the human immunodeficiency virus or HIV.

HIV is a member of the class of viruses known as retroviruses. Theretroviral genome is composed of RNA which is converted to DNA byreverse transcription. This retroviral DNA is then stably integratedinto a host cell's chromosome and, employing the replicative processesof the host cells, produces new retroviral particles and advances theinfection to other cells. HIV appears to have a particular affinity forthe human T-4 lymphocyte cell which plays a vital role in the body'simmune system. HIV infection of these white blood cells depletes thiswhite cell population. Eventually, the immune system is renderedinoperative and ineffective against various opportunistic diseases suchas, among others, pneumocystic carini pneumonia, Kaposi's sarcoma, andcancer of the lymph system.

Although the exact mechanism of the formation and working of the HIVvirus is not understood, identification of the virus has led to someprogress in controlling the disease. For example, the drugazidothymidine (AZT) has been found effective for inhibiting the reversetranscription of the retroviral genome of the HIV virus, thus giving ameasure of control, though not a cure, for patients afflicted with AIDS.The search continues for drugs that can cure or at least provide animproved measure of control of the deadly HIV virus.

Retroviral replication routinely features post-translational processingof polyproteins. This processing is accomplished by virally encoded HIVprotease enzyme. This yields mature polypeptides that will subsequentlyaid in the formation and function of infectious virus. If this molecularprocessing is stifled, then the normal production of HIV is terminated.Therefore, inhibitors of HIV protease may function as anti-HIV viralagents.

HIV protease is one of the translated products from the HIV structuralprotein pol gene. This retroviral protease specifically cleaves otherstructural polypeptides at discrete sites to release these newlyactivated structural proteins and enzymes, thereby rendering the virionreplication-competent. As such, inhibition of the HIV protease by potentcompounds may prevent proviral integration of infected T-lymphocytesduring the early phase of the HIV-I life cycle, as well as inhibit viralproteolytic processing during its late stage. Additionally, the proteaseinhibitors may have the advantages of being more readily available,longer lived in virus, and less toxic than currently available drugs,possibly due to their specificity for the retroviral protease.

Related inhibitors of HIV proteases have been described in, e.g., U.S.Pat. No. 5,962,640, U.S. Pat. No. 5,932,550, Australian Patent No.705193, Canadian Patent Application No. 2,179,935, Europan PatentApplication No. 0 751 145, and Japanese Patent Application No.100867489.Other related HIV protease inhibitors have been described in K.Yoshimura, et al., Proct. Natl. Acad. Sci. USA, 96, 8675-8680 (1999) andT. Mimoto, et al., J. Med. Chem., 42, 1789-1802 (1999).

On-going treatment of HIV-infected individuals with compounds thatinhibit HIV protease has led to the development of mutant viruses thatpossess protesases that are resistant to the inhibitory effect of thesecompounds. Thus, to be effective, new HIV protease inhibitors must beeffective not only against wild-type strains of HIV, but must alsodemonstrate efficacy against the newly emerging mutant strains that areresistant to the commercially available protease inhibitors.Accordingly, there continues to be a need for new inhibitors targetingthe HIV protease in both wild type and mutant strains of HIV.

SUMMARY OF THE INVENTION

This invention relates to compounds useful for inhibiting the activityof HIV-protease of Formula I:

wherein:

R¹ is an aliphatic, carbocyclic or heterocyclic group, or a group havingthe formula: OR^(1′), SR^(1′), NHR^(1′), N(R^(1′))R^(1″) or C(O)R^(1′),wherein R^(1′) is an aliphatic, carbocyclic or heterocyclic group, andR^(1″) is H or a C₁-C₆ aliphatic group or R^(1′) and R^(1″) togetherwith the atom to which they are attached form a substituted orunsubstituted heterocyclic ring;

V is C═O, C═S or SO₂;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, a heterocyclic-aliphatic group orN(R^(2a))R^(2b), wherein R^(2a) is an aliphatic, carbocyclic orheterocyclic group, and R^(2b) is H or a C₁-C₆ aliphatic group;

W is N, O, C or CH;

when W is N, C or CH, R^(2′) is H or a C₁-C₆ aliphatic group or R² andR^(2′) taken together with the atom W to which they are attached form anunsubstituted or substituted carbocyclic or heterocyclic ring;

when W is O, R^(2′) is absent;

X is

where Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group;

n is 0, 1 or 2;

R^(x) is H or one or more substituents independently selected from C₁-C₆alkyl, nitro, amino, cyano, halogen, C₁-C₆ haloalkyl, hydroxyl, C₁-C₆alkoxy, alkylenedioxy, C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl,C₁-C₆ alkylcarbonyloxy, carboxyl, carbamoyl, formyl, C₁-C₆ alkylamino,dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, di-C₁-C₆-alkylaminothiocarbonyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylcarbonylamino, C₁-C₆alkylthiocarbonylamino, C₁-C₆ alkylsulfonyloxy, C₁-C₆alkylsulfonylamino, mercapto, and C₁-C₆ alkylthio;

R⁸ and R^(8′) are each independently H, halo or a C₁-C₄ aliphatic group;

A is CH₂, CH(R^(A)) or is absent;

Z is S, O, SO, SO₂, CH₂, CHF, CF₂, CH(OH), CH(O—R^(Z)),CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), or CH(R^(Z)), where R^(Z) is aC₁-C₆ aliphatic group or a carbocyclic or heterocyclic group and R^(Z′)is H or a C₁-C₆ aliphatic group;

or R^(A) and R^(Z), taken together with A and Z form an unsubstituted orsubstituted 5 or 6 membered carbocyclic or heterocyclic ring;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ and R⁵ are independently selected from H, halo, a C₁-C₆ aliphaticgroup or a group having the formula C(O)R^(4′), wherein R^(4′) is analiphatic, carbocyclic or heterocyclic group;

or R⁴ and R⁵, taken together with the atom to which they are bound, forman unsubstituted or substituted carbocyclic ring;

or R⁴ and R⁶ or R⁷, together with the atoms to which they are bound,form an unsubstituted or substituted carbocyclic ring;

R⁶ and R⁷ are independently selected from H, halo or a C₁-C₆ aliphaticgroup;

or R⁶ and R⁷, taken together with the atom to which they are bound, forman unsubstituted or substituted carbocyclic or heterocyclic group;

wherein any of said aliphatic groups are saturated, partiallyunsaturated or fully unsaturated and unsubstituted or substituted by oneor more suitable substituents; and

wherein any of said carbocyclic or heterocyclic groups are unsubstitutedor substituted by one or more suitable substituents; saturated,partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic;

provided that R² is not an aliphatic group, a phenyl group or aphenyl-substituted aliphatic group when A is absent; Z is S, SO, SO₂,CHF, O or CH₂; V is C═O; W is N; R^(2′), R³, R⁸ and R^(8′) are H; R⁴,R⁵, R⁶ and R⁷ are H or a C₁-C₆ alkyl groups.

X is

wherein R^(x) is H; and R¹ is a substituted or unsubstituted 5 or6-membered mono-cyclic carbocyclic or heterocyclic group;

or provided that R² is not t-butyl when R¹ is substituted orunsubstituted phenyloxymethylene, orquinolylmethyenecarbonylaminomethylene; A is absent; Z is S; V is C═O; Wis N; R², R³, R⁴, R⁵, R⁸ and R^(8′) are H; R⁶ and R⁷ are H, methyl,ethyl or propyl; and X is

wherein R^(x) is H or methoxy.

The present invention relates to compounds of Formula I below, andprodrugs, pharmaceutically active metabolites, and pharmaceuticallyacceptable salts and solvates thereof that inhibit the protease encodedby human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2),as well as mutant strains thereof. These compounds are useful in thetreatment of infection by HIV and the treatment of the acquired immunedeficiency syndrome (AIDS). The compounds, their pharmaceuticallyacceptable salts, and the pharmaceutical compositions of the presentinvention can be used alone or in combination with other antivirals,immunomodulators, antibiotics or vaccines. Compounds of the presentinvention can also be converted to prodrugs, by derivatization,according to conventional techniques. Methods of treating AIDS, methodsof treating HIV infection and methods of inhibiting HIV protease aredisclosed.

DETAILED DESCRIPTION OF INVENTION AND PREFERRED EMBODIMENTS

In the compounds of this invention, the aliphatic groups are optionallysubstituted by one or more suitable substituents selected from aryl,cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halogen,hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy,heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl,alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl,cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl,heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl,heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy,heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo),thioketo, sulfo, alkylamino, cycloalkylamino, arylamino,heterocycloalkylamino, heteroarylamino, dialkylamino,alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl,dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio,heteroarylthio, wherein any of the alkyl, alkylene, aryl, cycloalkyl,heterocycloalkyl, heteroaryl moieties present in the above substituentsmay be further substituted. The alkyl, alkylene, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl moieties of any of the abovesubstituents may be optionally substituted by one or more of alkyl(except for alkyl), haloalkyl, aryl, nitro, amino, alkylamino,dialkylamino, halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto,alkylthio or arylthio groups.

In the compounds of this invention the substituted carbocyclic orheterocyclic groups may be optionally substituted by one or more of thefollowing: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, heteroaryl, nitro, amino, cyano,halogen, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, alkylenedioxy,aryloxy, cycloalkoxy, cycloalkenyloxy, heterocycloalkoxy,heterocycloalkenyloxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl,alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl,cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl,heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl,heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy,heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo),thioketo, sulfo, alkylamino, cycloalkylamino, arylamino,heterocycloalkylamino, heteroarylamino, dialkylamino,alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl,dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio,heteroarylthio, wherein any of the alkyl, alkylene, aryl, cycloalkyl,heterocycloalkyl, heteroaryl moieties present in the above substituentsmay be further substituted. Preferred “suitable substituents” includealkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,halogen, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy,heteroaryloxy, alkylthio, haloalkylthio and carboxyl. The alkyl,alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties ofany of the above substituents may be optionally substituted by one ormore of: alkyl, haloalkyl, nitro, amino, alkylamino, dialkylamino,halogen, hydroxyl, alkoxy, haloalkoxy, mercapto, alkylthio.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

As used herein, the term “aliphatic” represents a saturated orunsaturated, straight- or branched-chain hydrocarbon, containing 1 to 10carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. The term “aliphatic” is intended toencompass alkyl, alkenyl and alkynyl groups.

As used herein, the term “alkyl” represents a straight- orbranched-chain saturated or unsaturated hydrocarbon, containing 1 to 10carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. Exemplary alkyl substituents include,but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl,butyl, isobutyl, t-butyl, and the like. The term “lower alkyl” refers toan alkyl group containing from 1 to 6 carbon atoms

The term “alkenyl” represents a straight- or branched-chain hydrocarbon,containing one or more carbon-carbon double bonds and having 2 to 10carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. Exemplary alkenyl substituentsinclude, but-are not limited to ethenyl, propenyl, butenyl, allyl,pentenyl and the like.

The term “alkynyl” represents a straight- or branched-chain hydrocarbon,containing one or more carbon-carbon triple bonds and having 2 to 10carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. An alkynyl moiety may also contain oneor more carbon-carbon double bonds. Exemplary alkynyl substituentsinclude, but are not limited to ethynyl, butynyl, propynyl (propargyl)isopropynyl, pentynyl, hexynyl and the like.

The term “carbocyclic” represents a saturated, partially saturated, orfully unsaturated (aromatic) cyclic hydrocarbon group containing from 3to 14 carbon atoms which may be unsubstituted or substituted by one ormore of the substituents described herein below. The term “carbocyclic”is intended to encompass mono-, bi- and tri-cyclic saturated, partiallysaturated, or fully unsaturated hydrocarbon groups; for example,cycloalkyl, cycloalkenyl and aryl groups. The term “carbocyclic” is alsointended to encompass bi- and tri-cyclic hydrocarbon groups whichcontain any combination of ring moieties that are saturated, partiallysaturated, or fully unsaturated (aromatic). Partially saturatedcarbocycles include, for example, dihydroarenes (e.g., indanyl) ortetra-hydro-arenes (e.g. tetrahydronaphthalene), wherein any one or morepoints of saturation may occur in any ring moiety of the carbocycle. Inaddition, it is understood that bonding between any bi- or tri-cycliccarbocyclic group and any other substituent or variable group may bemade at any suitable position of the carbocycle. The term“carbocyclic-aliphatic” group is intended to encompass aliphatic groupshaving a carbocyclic substituent (e.g., phenylmethyl-(benzyl),phenylethyl-, cyclopropylmethyl-, etc.), wherein the carbocyclic moietyand the aliphatic moiety thereof may be independently substituted by oneor more suitable substituents.

“Cycloalkyl” represents a group comprising a non-aromatic monocyclic,bicyclic, or tricyclic hydrocarbon containing from 3 to 14 carbon atomswhich may be unsubstituted or substituted by one or more of thesubstituents described below. Exemplary cycloalkyls include monocyclicrings having from 3-8 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like. Illustrative examplesof cycloalkyl groups include the following:

“Cycloalkenyl” represents a group comprising a non-aromatic monocyclic,bicyclic, or tricyclic hydrocarbon containing from 4 to 14 carbon atomswhich may be unsubstituted or substituted by one or more of thesubstituents described below and contains at least one carbon-carbondouble bond. Exemplary monocyclic cycloalkenyls include groups havingfrom 4-8, preferably 5-6, carbon atoms, such as cyclopentenyl,cyclopentadienyl, cyclohexenyl, cycloheptenyl and the like. Illustrativeexamples of cycloalkenyl groups include the following:

“Aryl” represents a group comprising an aromatic, monovalent monocyclic,bicyclic, or tricyclic radical containing from 6 to 18 carbon ringatoms, which may be unsubstituted or substituted by one or more of thesubstituents described below. Illustrative examples of aryl groupsinclude the following:

The term “carbocyclic” also to encompasses mixed bi- and tricycliccycloalkyl/cycloalkenyl/aryl groups, which may be unsubstituted orsubstituted by one or more of the substituents described below.Illustrative examples of such mixed bi-and tri-cyclic groups include thefollowing:

It is understood that bonding or substitution of any bi-cyclic ortri-cyclic carbocyclic or heterocyclic group described herein may be atany suitable position on any ring. Illustrative examples of such bondingin mixed bi-and tri-cyclic carbocyclic groups include the following:

wherein R¹ is any suitable substituent.

The term “heterocyclic” represents a saturated, partially saturated, orfully unsaturated (aromatic) cyclic group containing from 3 to 18 ringatoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygenand sulfur, and which may be unsubstituted or substituted by one or moreof the substituents described herein below. The term “heterocyclic” isintended to encompass mono-, bi- and tri-cyclic saturated, partiallysaturated, or fully unsaturated heteroatom-containing cyclic groups; forexample, heterocycloalkyl, heterocycloalkenyl and heteroaryl groups. Theterm “heterocyclic” is also intended to encompass bi- and tri-cyclicgroups which contain any combination of ring moieties that aresaturated, partially saturated, or fully unsaturated (aromatic).Partially saturated heterocycles include, for example,dihydroheteroarenes (e.g., dihydroindole) or tetrahydro-heteroarenes(e.g. tetrahydroquinoline), wherein any one or more points of saturationmay occur in any ring moiety of the heterocycle. In addition, it isunderstood that bonding between any bi- or tri-cyclic heterocyclic groupand any other substituent or variable group may be made at any suitableposition of the heterocycle (i.e., there is no restriction that asubstituent or variable group must be bonded to theheteroatom-containing moiety of a bi- or tri-cyclic heterocyclic group).The term “heterocyclic-aliphatic” group is intended to encompassaliphatic groups having a heterocyclic substituent (e.g.,pyridylmethyl-, thiazolylmethyl-, tetrahydrofuranylmethyl-, etc.)wherein the heterocyclic moiety and the aliphatic moiety thereof may beindependently substituted by one or more suitable substituents.

“Heterocycloalkyl” represents a group comprising a saturated monovalentmonocyclic, bicyclic, or tricyclic radical, containing 3 to 18 ringatoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygenand sulfur, and which may be unsubstituted or substituted by one or moreof the substituents described below. Illustrative examples ofheterocycloalkyl groups include, but are not limited to, azetidinyl,pyrrolidyl, piperidyl, piperazinyl, morpholinyl,tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, tetrahydropyranyl,1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl,1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl,azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl,1,5,9-triazacyclododecyl, and the like. Illustrative examples ofheterocycloalkyl groups include the following:

wherein R is H, alkyl, hydroxyl or represents a compound according toFormula I, and the bond depicted as

, represents bonding to either face of the bi-cyclic moiety (i.e., endoor exo).

The term “heterocycloalkenyl” is used herein to represent anon-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical,containing 4 to 18 ring atoms, which may include from 1 to 5 heteroatomsselected from nitrogen, oxygen and sulfur, and which may beunsubstituted or substituted by one or more of the substituentsdescribed below and which contains at least one carbon-carbon orcarbon-heteroatom double bond. Exemplary monocyclic heterocycloalkenylsinclude groups having from 4-8, preferably 5-6, ring atoms. Illustrativeexamples of heterocycloalkenyl groups include, but are not limited to,dihydrofuryl, dihydropyranyl, isoxazolinyl, dihydropyridyl,tetrahydropyridyl, and the like. Illustrative examples ofheterocycloalkenyl groups include the following:

wherein R is H, alkyl, hydroxyl or represents a compound according toFormula I.

“Heteroaryl” represents a group comprising an aromatic monovalentmonocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ringatoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen andsulfur, which may be unsubstituted or substituted by one or more of thesubstituents described below. As used herein, the term “heteroaryl” isalso intended to encompass the N-oxide derivative (or N-oxidederivatives, if the heteroaryl group contains more than one nitrogensuch that more than one N-oxide derivative may be formed) of thenitrogen-containing heteroaryl groups described herein. Illustrativeexamples of heteroaryl groups include, but are not limited to, thienyl,pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl,isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl,chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl,indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl,tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, andphenoxazinyl. Illustrative examples of N-oxide derivatives of heteroarylgroups include, but are not limited to, pyridyl N-oxide, pyrazinylN-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide,isoquinolyl N-oxide, and quinolyl N-oxide. Further examples ofheteroaryl groups include the following moieties:

wherein R is H, alkyl, hydroxyl or represents a compound according toFormula I.

The term “heterocyclic” also to encompasses mixed bi- and tri-cyclicheterocycloalkyl/heterocycloalkenyl/heteroaryl groups, which may beunsubstituted or substituted by one or more of the substituentsdescribed below. Illustrative examples of such mixed bi-and tri-cyclicheterocyclic groups include the following:

Illustrative examples of such bonding in mixed bi-and tricyclicheterocyclic groups include the following:

wherein R′ is any suitable substituent.

Unless otherwise stated, exemplary “suitable substituents” that may bepresent on any of the above aliphatic, carbocyclic, heterocyclic, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl or heteroaryl groups, described herein, include alkyl(except for alkyl), aryl, cycloalkyl, heterocycloalkyl, heteroaryl,nitro, amino, cyano, halogen, hydroxyl, alkoxy, alkylenedioxy, aryloxy,cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy,aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy,cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy,heteroaryloxycarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl,carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino,cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino,dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl,arylaminocarbonyl, heterocycloalkylaminocarbonyl,heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino,alkylthiocarbonylamino, cycloalkylthiocarbonylamino,arylthiocarbonylamino, heterocycloalkylthiocarbonylamino,heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy,alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio,heteroarylthio, wherein any of the alkyl, alkylene, aryl, cycloalkyl,heterocycloalkyl, heteroaryl moieties present in the above substituentsmay be further substituted. The alkyl, alkylene, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl moieties of any of the abovesubstituents may be optionally substituted by one or more of alkyl(except for alkyl), haloalkyl, aryl, nitro, amino, alkylamino,dialkylamino, halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto,alkylthio or arylthio groups.

If the substituents themselves are not compatible with the syntheticmethods of this invention, the substituent may be protected with asuitable protecting group that is stable to the reaction conditions usedin these methods. The protecting group may be removed at a suitablepoint in the reaction sequence of the method to provide a desiredintermediate or target compound. Suitable protecting groups and themethods for protecting and de-protecting different substituents usingsuch suitable protecting groups are well known to those-skilled in theart; examples of which may be found in T. Greene and P. Wuts, ProtectingGroups in Chemical Synthesis (3^(rd) ed.), John Wiley & Sons, NY (1999),which is incorporated herein by reference in its entirety. In someinstances, a substituent may be specifically selected to be reactiveunder the reaction conditions used in the methods of this invention.Under these circumstances, the reaction conditions convert the selectedsubstituent into another substituent that is either useful in anintermediate compound in the methods of this invention or is a desiredsubstituent in a target compound.

In the compounds of this invention, R² and R^(2′), independently ortaken together, may be a suitable nitrogen protecting group. Asindicated above, nitrogen protecting groups are well known in the artand any nitrogen protecting group that is useful in the methods ofpreparing the compounds of this invention or may be useful in the HIVprotease inhibitory compounds of this invention may be used. Exemplarynitrogen protecting groups include alkyl, substituted alkyl, carbamate,urea, amide, imide, enamine, sulfenyl, sulfonyl, nitro, nitroso, oxide,phosphinyl, phosphoryl, silyl, organometallic, borinic acid and boronicacid groups. Examples of each of these groups, methods for protectingnitrogen moieties using these groups and methods for removing thesegroups from nitrogen moieties are disclosed in T. Greene and P. Wuts,supra. Preferably, when R² and/or R^(2′) are independently suitablenitrogen protecting groups, suitable R² and R^(2′) substituents include,but are not limited to, carbamate protecting groups such asalkyloxycarbonyl (e.g., Boc: t-butyloxycarbonyl) and aryloxycarbonyl(e.g., Cbz: benzyloxycarbonyl, or FMOC: fluorene-9-methyloxycarbonyl),alkyloxycarbonyls (e.g., methyloxycarbonyl), alkyl or arylcarbonyl,substituted alkyl, especially arylalkyl (e.g., trityl (triphenylmethyl),benzyl and substituted benzyl), and the like. When R² and R^(2′) takentogether are a suitable nitrogen protecting group, suitable R²/R^(2′)substituents include phthalimido and a stabase(1,2-bis(dialkylsilyl))ethylene).

The terms “halogen” and “halo” represent chloro, fluoro, bromo or iodosubstituents. “Heterocycle” is intended to mean a heteroaryl orheterocycloalkyl group. “Acyl” is intended to mean a —C(O)—R radical,where R is a substituted or unsubstituted alkyl, cycloalkyl, aryl,heterocycloalkyl or heteroaryl group. “Acyloxy” is intended to mean an—OC(O)—R radical, where R is a substituted or unsubstituted alkyl,cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. “Thioacyl” isintended to mean a —C(S)—R radical, where R is a substituted orunsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroarylgroup. “Sulfonyl” is intended to mean an —SO₂— biradical. “Sulfenyl” isintended to mean an —SO— biradical. “Sulfo” is intended to mean an —SO₂Hradical. “Hydroxy” is intended to mean the radical —OH. “Amine” or“amino” is intended to mean the radical —NH₂. “Alkylamino” is intendedto mean the radical —NHR_(a), where R_(a) is an alkyl group.“Dialkylamino” is intended to mean the radical —NR_(a)R_(b), where R_(a)and R_(b) are each independently an alkyl group, and is intended toinclude heterocycloalkyl groups, wherein R_(a) and R_(b), takentogether, form a heterocyclic ring that includes the amine nitrogen.“Alkoxy” is intended to mean the radical —OR_(a), where R_(a) is analkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy,and the like. “Lower alkoxy” groups have alkyl moieties having from 1 to4 carbons. “Alkoxycarbonyl” is intended to mean the radical —C(O)OR_(a),where R_(a) is an alkyl group. “Alkylsulfonyl” is intended to mean theradical —SO₂R_(a), where R_(a) is an alkyl group. “Alkylenedioxy” isintended to mean the divalent radical —OR_(a)O— which is bonded toadjacent atoms (e.g., adjacent atoms on a phenyl or naphthyl ring),wherein R_(a) is a lower alkyl group. “Alkylaminocarbonyl” is intendedto mean the radical —C(O)NHR_(a), where R_(a) is an alkyl group.“Dialkylaminocarbonyl” is intended to mean the radical —C(O)NR_(a)R_(b),where R_(a) and R_(b) are each independently an alkyl group. “Mercapto”is intended to mean the radical —SH. “Alkylthio” is intended to mean theradical —SR_(a), where R_(a) is an alkyl group. “Carboxy” is intended tomean the radical —C(O)OH. “Keto” or “oxo” is intended to mean thediradical ═O. “Thioketo” is intended to mean the diradical ═S.“Carbamoyl” is intended to mean the radical —C(O)NH₂. “Cycloalkylalkyl”is intended to mean the radical-alkyl-cycloalkyl, wherein alkyl andcycloalkyl are defined as above, and is represented by the bondingarrangement present in the groups —CH₂-cyclohexane or —CH₂-cyclohexene.“Arylalkyl” is intended to mean the radical-alkylaryl, wherein alkyl andaryl are defined as above, and is represented by the bonding arrangementpresent in a benzyl group. “Aminocarbonylalkyl” is intended to mean theradical-alkylC(O)NH₂ and is represented by the bonding arrangementpresent in the group —CH₂CH₂C(O)NH₂. “Alkylaminocarbonylalkyl” isintended to mean the radical-alkylC(O)NHR_(a), where R_(a) is an alkylgroup and is represented by the bonding arrangement present in the group—CH₂CH₂C(O)NHCH₃. “Alkylcarbonylaminoalkyl is intended to mean theradical-alkylNHC(O)-alkyl and is represented by the bonding arrangementpresent in the group —CH₂NHC(O)CH₃. “Dialkylaminocarbonylalkyl” isintended to mean the radical-alkylC(O)NR_(a)R_(b), where R_(a) and R_(b)are each independently an alkyl group. “Aryloxy” is intended to mean theradical —OR_(c), where R_(c) is an aryl group. “Heteroaryloxy” isintended to mean the radical —OR_(d), where R_(d) is a heteroaryl group.“Arylthio” is intended to mean the radical —SR_(c), where R_(c) is anaryl group. “Heteroarylthio” is intended to mean the radical —SR_(d),where R_(d) is a heteroaryl group.

One embodiment of this invention comprises the compounds depicted byFormula I-A:

wherein:

R¹ is an aliphatic group, a bi- or tri- cyclic carbocyclic orheterocyclic group or a group having the formula: OR^(1′), SR^(1′),NHR^(1′), N(R^(1′))R^(1″) or C(O)R^(1′), wherein R^(1′) is an aliphatic,carbocyclic or heterocyclic group, and R^(1″) is H or a C₁-C₆ aliphaticgroup or R^(1′) and R^(1″) together with the atom to which they areattached form a substituted or unsubstituted heterocyclic ring;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

R² is H or a C₁-C₆ alkyl group;

or R² and R^(2′) taken together with the nitrogen atom to which they areattached form an unsubstituted or substituted carbocyclic orheterocyclic ring;

X is

wherein Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group, wherein R^(x) is H or one or more substituentsindependently selected from alkyl, nitro, amino, cyano, halogen,haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl,alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl,alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino,alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

n is 1 or 2;

R⁸ and R^(8′) are each independently H, halo or a C₁-C₄ aliphatic group;

Z is S, O, SO, SO₂, CH₂, CHF, CF₂, CH(OH), CH(O—R^(Z)),CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), or CH(R^(Z)), where R^(Z) is aC₁-C₆ aliphatic group or a carbocyclic or heterocyclic group and R^(Z′)is H or a C₁-C₆ aliphatic group;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ and R⁵ are independently selected from H, halo, a C₁-C₆ aliphaticgroup or a group having the formula C(O)R^(4′), wherein R^(4′)is analiphatic, carbocyclic or heterocyclic group;

R⁶ and R⁷ are independently selected from H, halo or a C₁-C₆ aliphaticgroup;

wherein any of said aliphatic groups are unsubstituted or substituted byone or more suitable substituents and saturated, partially unsaturatedor fully unsaturated; and

wherein any of said carbocyclic or heterocyclic groups are mono-, bi- ortricyclic; saturated, partially unsaturated or fully unsaturated; orunsubstituted or substituted by one or more suitable substituents.

provided that R² is not an aliphatic group, a phenyl group or aphenyl-substituted aliphatic group, when A is absent; Z is S, SO, SO₂,CHF, O, or CH₂; V is C═O; W is N; R^(2′), R³, R⁸ and R^(8′) are H or aC₁-C₄ alkyl group; R⁴, R⁵, R⁶ and R⁷ are H or a C₁-C₆ alkyl group; X is

R¹ is a substituted or unsubstituted 5 or 6-membered mono-cycliccarbocyclic or heterocyclic group;

Another embodiment of this invention comprises the compounds depicted byFormula I-A, wherein:

R¹ is a 3-, 4-, or 7-membered mono-cyclic carbocyclic or heterocyclicgroup.

In another embodiment, the compounds of this invention are depicted byFormula I-A, wherein:

R¹ is a 5- or 6-membered monocyclic carbocyclic or heterocyclic group;and

R² is cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, abi- or tri-cyclic carbocyclic group, a bi- or tri-cycliccarbocyclic-alkyl group, a bi- or tricyclic carbocyclic-alkenyl group, abi- or tri-cyclic carbocyclic-alkynyl group, a heterocyclic group, aheterocyclic-alkyl group, a heterocyclic-alkenyl group or aheterocyclic-alkynyl group;

Another embodiment of this invention relates to compounds useful forinhibiting the activity of HIV-protease having Formula I-A, wherein:

R¹ is an aliphatic, carbocyclic or heterocyclic group, or a group havingthe formula: OR^(1′), SR^(1′), NHR¹, N(R^(1′))R^(1″) or C(O)R^(1′),wherein R^(1′) is an aliphatic, carbocyclic or heterocyclic group, andR^(1″) is H or a C₁-C₆ aliphatic group or R^(1′) and R^(1″) togetherwith the atom to which they are attached form a substituted orunsubstituted heterocyclic ring;

X is

where Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group, n is 0, 1 or 2 and R^(x) is H or one or more suitablesubstituents independently selected from C₁-C₆ alkyl, nitro, amino,cyano, halogen, C₁-C₆ haloalkyl, hydroxyl, C₁-C₆ alkoxy, alkylenedioxy,C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl, C₁-C₆ alkylcarbonyloxy,carboxyl, carbamoyl, formyl, C₁-C₆ alkylamino, di-C₁-C₆ alkylamino,C₁-C₆ alkylaminocarbonyl, di-C₁-C₄ alkylaminocarbonyl, C₁-C₆alkylaminothiocarbonyl, di-C₁-C₆-alkylaminothiocarbonyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylcarbonylamino, C₁-C₆alkylthiocarbonylamino, C₁-C₆ alkylsulfonyloxy, C₁-C₆alkylsulfonylamino, mercapto, C₁-C₆ alkylthio and halo-C₁-C₆ alkylthio;and

R⁸ and R^(8′) are each independently H, halo or a C₁-C₄ aliphatic groupprovided that R⁸ and R^(8′) are not both H when X is

Another embodiment of this invention relates to compounds depicted byFormula I-A, wherein:

R¹ is a bi- or tri-cyclic carbocyclic or heterocyclic group, whereinsaid carbocyclic or heterocyclic group is saturated, partiallyunsaturated or fully unsaturated; and unsubstituted or substituted byone or more suitable substitutents.

A specific embodiment of a compound of Formula I-A of this invention,wherein Z is S and R^(2′), R⁸ and R^(8′) are each H, may be representedas follows:

wherein the formula variables are as defined in Formula I-A, above.

Another embodiment of this invention comprises the compounds depicted byFormula I-B:

wherein

R¹ is an aliphatic, carbocyclic or heterocyclic group, or a group havingthe formula: OR^(1′), SR^(1′), NHR^(1′), N(R^(1′))R^(1″) or C(O)R^(1′),wherein R^(1′) is an aliphatic, carbocyclic or heterocyclic group, andR^(1″) is H or a C₁-C₆ aliphatic group or R^(1′) and R^(1″) togetherwith the atom to which they are attached form a substituted orunsubstituted heterocyclic ring;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

R^(2′) is H or a C₁-C₆ aliphatic group;

X is

wherein Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group; n is 1 or 2; and R^(x) is H or one or more suitablesubstituents independently selected from alkyl, nitro, amino, cyano,halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl,alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl,alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino,alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

R⁸ and R^(8′) are each independently H, halo or a C₁-C₄ aliphatic group;

Z is S, O, SO, SO₂, CH₂, CHF, CF₂, CH(OH), CH(O—R^(Z)),CH(N-R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), or CH(R^(Z)), where R^(Z) is aC₁-C₆ aliphatic group or a carbocyclic or heterocyclic group and R^(Z′)is H or a C₁-C₆ aliphatic group;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ and R⁵ are independently selected from H, halo, a C₁-C₆ aliphaticgroup or a group having the formula C(O)R^(4′), wherein R^(4′) is analiphatic, carbocyclic or heterocyclic group;

R⁶ and R⁷ are independently selected from H, halo or a C₁-C₆ aliphaticgroup;

where any of said aliphatic groups are saturated, partially unsaturatedor fully unsaturated and unsubstituted or substituted by one or moresuitable substituents; and

where any of said carbocyclic or heterocyclic groups are optionallyunsubstituted, substituted by one or more suitable substituents;saturated, partially unsaturated or fully unsaturated; or mono-, bi- ortri-cyclic.

A specific embodiment of a compound of Formula I-B of this invention,wherein Z is S and R^(2′), R⁸ and R^(8′) are each H, may be representedas follows:

wherein the formula variables are as defined in Formula I-B, above.

In yet another embodiment, the compounds of this invention useful forinhibiting the activity of HIV-protease have the Formula I-C:

wherein

R¹ is an aliphatic, carbocyclic or heterocyclic group, or a group havingthe formula: OR^(1′), SR^(1′), NHR^(1′), N(R^(1′))R′ or C(O)R^(1′),wherein R^(1′) is an aliphatic, carbocyclic or heterocyclic group, andR^(1″) is H or a C₁-C₆ aliphatic group or R^(1′) and R^(1″) togetherwith the atom to which they are attached form a substituted orunsubstituted heterocyclic ring;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

W is N, O or C;

when W is N or C, R^(2′) is H or a C₁-C₆ alkyl group or R² and R^(2′)taken together with the atom W to which they are attached form anunsubstituted or substituted carbocyclic or heterocyclic ring;

when W is O, R^(2′) is absent;

X is

wherein Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group; n is 1 or 2; and R^(x) is H or one or more substituentsindependently selected from alkyl, nitro, amino, cyano, halogen,haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, fonnyl,alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl,alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino,alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

R⁸ and R^(8′) are each independently H, halo or a C₁-C₄ aliphatic group;

Z is CF₂, CH(OH), CH(O—R^(Z)) or CH(R^(Z)), where R^(Z) is a C₁-C₆aliphatic group or a carbocyclic or heterocyclic group;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ and R⁵ are independently selected from H, halo, a C₁-C₆ aliphaticgroup or a group having the formula C(O)R^(4′), wherein R^(4′) is analiphatic, carbocyclic or heterocyclic group;

R⁶ and R⁷ are independently selected from H, halo or a C₁-C₆ aliphaticgroup;

where any of said aliphatic groups are saturated, partially unsaturatedor fully unsaturated and unsubstituted or substituted by one or moresuitable substituents; and

where any of said carbocyclic or heterocyclic groups are unsubstitutedor substituted by one or more suitable substituents; saturated,partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

A specific embodiment of a compound of Formula I-C of this invention,wherein Z is CF₂ and R⁸ and R^(8′) are each H, may be represented asfollows:

wherein the formula variables are as defined in Formula I-C, above.

Another embodiment of this invention comprises the compounds depicted bythe Formula I-D, as follows:

wherein

R¹ is an aliphatic, carbocyclic or heterocyclic group, or a group havingthe formula: OR^(1′), SR^(1′), NHR^(1′), N(R^(1′))R^(1″) or C(O)R^(1′),wherein R^(1′) is an aliphatic, carbocyclic or heterocyclic group, andR^(1″) is H or a C₁-C₆ aliphatic group or R^(1′) and R^(1″) togetherwith the atom to which they are attached form a substituted orunsubstituted heterocyclic ring;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

W is N, O or C;

when W is N or C, R^(2′) is H or a C₁-C₆ alkyl group or R² and R^(2′)taken together with the atom W to which they are attached form anunsubstituted or substituted carbocyclic or heterocyclic ring;

when W is O, R^(2′) is absent;

X is

wherein Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group; n is 1 or 2; and R^(x) is H or one or more suitablesubstituents independently selected from alkyl, nitro, amino, cyano,halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl,alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl,alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino,alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

R⁸ and R^(8′) are each independently H, halo or a C₁-C₄ aliphatic group;

Z is S, O, SO, SO₂, CHF, CH₂, CF₂, CH(OH), CH(O—R^(Z)),CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), or CH(R^(Z)), where R^(Z) is aC₁-C₆ aliphatic group or a carbocyclic or heterocyclic group and R^(Z′)is H or a C₁-C₆ aliphatic group;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ and R⁵ are independently selected from H, halo, a C₁-C₆ aliphaticgroup or a group having the formula C(O)R^(4′), wherein R^(4′) is analiphatic, carbocyclic or heterocyclic group;

R⁶ and R⁷ are independently selected from H, halo or a C₁-C₆ aliphaticgroup;

where any of said aliphatic groups are saturated, partially unsaturatedor fully unsaturated and unsubstituted or substituted by one or moresuitable substituents; and

where any of said carbocyclic or heterocyclic groups are unsubstitutedor substituted by one or more suitable substituents; saturated,partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

Another embodiment of this invention comprises the compounds depicted bythe Formula I-E, as follows:

wherein

R¹ is an aliphatic, carbocyclic or heterocyclic group, or a group havingthe formula: OR^(1′), SR^(1′), NHR^(1′), N(R^(1′))R^(1″) or C(O)R^(1′),wherein R^(1′) is an aliphatic, carbocyclic or heterocyclic group, andR^(1″) is H or a C₁-C₆ aliphatic group or R^(1′) and R^(1″) togetherwith the atom to which they are attached form a substituted orunsubstituted heterocyclic ring;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

W is N, O or C;

when W is N or C, R^(2′) is H or a C₁-C₆ alkyl group or R² and R^(2′)taken together with the atom W to which they are attached form anunsubstituted or substituted carbocyclic or heterocyclic ring;

when W is O, R^(2′) is absent;

X is

wherein Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group, wherein R^(x) is H or one or more suitable substituentsindependently selected from alkyl, nitro, amino, cyano, halogen,haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl,alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl,alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino,alkylsulfonyloxy, alkylsulfonylamino, mercapto, alkylthio;

R⁸ and R^(8′) are each independently H, halo or a C₁-C₄ aliphatic group;

Z is S, O, SO, SO₂, CH₂, CHF, CF₂, CH(OH), CH(O—R^(Z)),CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), or CH(R^(Z)), where R^(Z) is aC₁-C₆ aliphatic group or a carbocyclic or heterocyclic group and R^(Z′)is H or a C₁-C₆ aliphatic group;

n is 1 or 2;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ is selected from H, halo, a C₁-C₆ aliphatic group or a group havingthe formula C(O)R^(4′), wherein R^(4′) is an aliphatic, carbocyclic orheterocyclic group;

R⁷ is H, halo or a C₁-C₆ aliphatic group;

where any of said aliphatic groups are saturated, partially unsaturatedor fully unsaturated and unsubstituted or substituted by one or moresuitable substituents; and

where any of said carbocyclic or heterocyclic groups are unsubstituted,substituted by one or more suitable substituents; saturated, partiallyunsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

A specific embodiment of s compound of Formula I-E, wherein n is 2 andR⁸ and R^(8′) are each H, may be represented as follows:

wherein the formula variables are as defined above.

Another embodiment of this invention comprises the compounds of FormulaI, wherein A is CH(R^(A)), Z is CH(R^(Z)) and R^(A) and R^(Z) takentogether form a 5 or 6-membered carbocyclic ring, depicted by theFormula I-F, as follows:

wherein

R¹ is an aliphatic, carbocyclic or heterocyclic group, or a group havingthe formula: OR^(1′), SR^(1′), NHR^(1′), N(R^(1′))R^(1″) or C(O)R^(1′),wherein R^(1′) is an aliphatic, carbocyclic or heterocyclic group, andR^(1″) is H or a C₁-C₆ aliphatic group or R^(1′) and R^(1″) togetherwith the atom to which they are attached form a substituted orunsubstituted heterocyclic ring;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

W is N, O or C;

when W is N or C, R^(2′) is H or a C₁-C₆ alkyl group or R² and R^(2′)taken together with the atom W to which they are attached form anunsubstituted or substituted carbocyclic or heterocyclic ring;

when W is O, R^(2′) is absent;

X is

wherein Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group, wherein R^(x) is H or one or more substituentsindependently selected from alkyl, nitro, amino, cyano, halogen,haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl,alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl,alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino,alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

n is 1 or 2;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ and R⁵ are independently selected from H, halo, a C₁-C₆ aliphaticgroup or a group having the formula C(O)R^(4′), wherein R^(4′) is analiphatic, carbocyclic or heterocyclic group;

R⁶ and R⁷ are independently selected from H, halo or a C₁-C₆ aliphaticgroup;

R⁸ and R^(8′) are each independently H, halo or a C₁-C₄ aliphatic group;

where any of said aliphatic groups ar saturated, partially unsaturatedor fully unsaturated and unsubstituted or substituted by one or moresuitable substituents; and

where any of said carbocyclic or heterocyclic groups are unsubstitutedor substituted by one or more suitable substituents; saturated,partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

A specific embodiment of a compound of Formula I-F, wherein n is 2 andR⁸ and R^(8′) are each H, may be represented as follows:

wherein the formula variables are as defined above.

In one embodiment, the compounds of Formula I-A of this invention,wherein R⁶ and R⁷, taken together with the atom to which they are bound,form a carbocyclic group, comprise spiro-fused bi-cyclic compoundshaving the Formula I-G:

wherein

R¹ is an aliphatic, carbocyclic or heterocyclic. group, or a grouphaving the formula: OR^(1′), SR^(1′), NHR^(1′), N(R^(1′))R^(1″) orC(O)R^(1′), wherein R^(1′) is an aliphatic, carbocyclic or heterocyclicgroup, and R^(1″) is H or a C₁-C₆ aliphatic group or R^(1′) and R^(1″)together with the atom to which they are attached form a substituted orunsubstituted heterocyclic ring;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

W is N, O or C;

when W is N or C, R^(2′) is H or a C₁-C₆ alkyl group or R² and R^(2′)taken together with the atom W to which they are attached form anunsubstituted or substituted carbocyclic or heterocyclic ring.

when W is O, R^(2′) is absent;

X is

wherein Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group, wherein R^(x) is H or one or more substituentsindependently selected. from alkyl, nitro, amino, cyano, halogen,haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl,alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl,alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino,alkylsulfonyloxy, alkylsulfonylamino, mercapto, alkylthio;

R⁸ and R^(8′) are each independently H, halo or a C₁-C₄ aliphatic group;

Z is S, O, SO, SO₂, CHF, CH₂, CF₂, CH(OH), CH(O—R^(Z)),CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), or CH(R^(Z)), where R^(Z) is aC₁-C₆ aliphatic group or a carbocyclic or heterocyclic group and R^(Z′)is H or a C₁-C₆ aliphatic group;

n is 1, 2, 3 or 4;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ and R⁵ are independently selected from H, halo, a C₁-C₆ aliphaticgroup or a group having the formula C(O)R^(4′), wherein R^(4′) is analiphatic, carbocyclic or heterocyclic group;

where any of said aliphatic groups are saturated, partially unsaturatedor fully unsaturated and unsubstituted or substituted by one or moresuitable substituents; and

where any of said carbocyclic or heterocyclic groups are unsubstituted,substituted by one or more suitable substituents; saturated, partiallyunsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

In the compounds of this inventions, R² may consist of a substitutedaliphatic group; wherein R² may be represented as —CH₂—B, —CH₂CH₂—B,—CH(CH₃)B, and the like, wherein B is a carbocyclic or heterocyclicgroup as described herein, and wherein the B group may be unsubstitutedor substituted with one or more substituents selected from C₁-C₄ alkyl,halo, haloalkyl, hydroxy, alkoxy, halo alkoxy, alkylthio, haloalkylthio,amino, dialkylamino, alkyl-SO₂, cyano, alkylcarbonylamino andcycloalkylalkyloxy.

Specific embodiments of the compounds of this invention comprise thecompounds depicted by Formula I-A′:

wherein:

R¹ is an alkyl, alkenyl, or alkynyl group, a bi- or tri-cycliccycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl orheteroaryl group or a group having the formula: OR^(1′), SR^(1′),NHR^(1′), N(R^(1′))R^(1″) or C(O)R^(1′), wherein R^(1′) is an alkyl,alkenyl, or alkynyl group, a bi- or tri-cyclic cycloalkyl, cycloalkenyl,aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group, or acycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heterocycloalkylalkyl,heterocycloalkenylalkyl, heteroarylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, arylalkenyl, heterocycloalkylalkenyl,heterocycloalkenylalkenyl, heteroarylalkenyl, cycloalkylalkynyl,cycloalkenylalkynyl, arylalkynyl, heterocycloalkylalkynyl,heterocycloalkenylalkynyl, or heteroarylalkynyl group; and R^(1″) is Hor a C₁-C₆ alkyl, alkenyl or alkynyl group or R^(1′) and R^(1″) togetherwith the atom to which they are attached form a substituted orunsubstituted heterocyclic ring;

R² is a cycloalkyl, cycloalkylalkyl, cycloalkenyl, or cycloalkenylalkylgroup, a bi- or tri-cyclic aryl group, a bi- or tri-cyclic arylalkylgroup, a bi- or tri-cyclic arylalkenyl group, a bi- or tri-cyclicarylalkynyl group, or a heterocycloalkyl, heterocycloalkylalkyl,heterocycloalkenyl, heterocycloalkenylalkyl, heteroaryl orheteroarylalkyl group;

R^(2′) is H or a C₁-C₆ alkyl group;

or R² and R^(2′) taken together with the nitrogen atom to which they areattached form a heterocycloalkyl or heterocycloalkenyl ring;

X is

wherein Y′ and Y″ are independently selected from H, halo, or a C₁-C₆aliphatic group, wherein R^(x) is H or one or more substituentsindependently selected from alkyl, nitro, amino, cyano, halogen,haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, fonnyl,alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl,alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino,alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

Z is S, O, SO, SO₂, CH₂, CHF, CF₂, CH(OH), CH(O—R^(Z)),CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), or CH(R^(Z)), where R^(Z) is aC₁-C₆ aliphatic group or a carbocyclic or heterocyclic group and R^(Z′)is H or a C₁-C₆ aliphatic group;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ and R⁵ are independently selected from H, halo, and a C₁-C₆ aliphaticgroup;

R⁶ and R⁷ are independently selected from H, halo and a C₁-C₆ aliphaticgroup;

where any of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups or thealkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocycloalkyl, heterocycloalkenyl or heteroaryl moieties of thecycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heterocycloalkylalkyl,heterocycloalkenylalkyl, heteroarylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, arylalkenyl, heterocycloalkylalkenyl,heterocycloalkenylalkenyl, heteroarylalkenyl, cycloalkylalkynyl,cycloalkenylalkynyl, arylalkynyl, heterocycloalkylalkynyl, andheterocycloalkenylalkynyl, heteroarylalkynyl groups are unsubstituted orsubstituted by one or more suitable substituents; and

where any of said carbocyclic or heterocyclic groups are optionallymono-, bi- or tri-cyclic; saturated, partially unsaturated or fullyunsaturated; and unsubstituted or substituted by one or more suitablesubstituents.

provided that R² is not an aliphatic group, a phenyl group, or aphenyl-substituted aliphatic group, when Z is S, SO, SO₂, CHF, O,or CH₂;R^(2′), R³, R⁸ and R^(8′) are H or a C₁-C₄ alkyl group; R⁴, R⁵, R⁶ andR⁷ are H or a C₁-C₆ alkyl group; X is

R¹ is a substituted or unsubstituted 5 or 6-membered mono-cycliccarbocyclic or heterocyclic group;

or provided that R² is not t-butyl when R¹ is substituted orunsubstituted phenyloxymethylene, orquinolylmethylenecarbonylaminomethylene; A is absent; Z is S; R^(2′),R³, R⁴, and R⁵, are H; R⁶ and R⁷ are H, methyl, ethyl or propyl; and Xis

wherein R^(x) is H or methoxy,

In another embodiment, the compounds of this invention are depicted byFormula I-A; wherein:

Z is CF₂, CH(OH), CH (OR^(Z)), CH(NR^(Z)R^(Z′)), CH(S—R^(Z)), C═O orCH(R^(Z)), where R^(Z) is a C₁-C₆ aliphatic group or a carbocyclic orheterocyclic group and R^(Z′) is H or a C₁-C₆ aliphatic group.

Specific examples of the compounds of Formula I-B comprise compoundshaving the formula I-B′

wherein

R¹ is an aliphatic, carbocyclic or heterocyclic group,

R² is an aliphatic group, a carbocyclic-aliphatic group, or aheterocyclic-aliphatic group;

R^(2′) is H or a C₁-C₆ alkyl group;

or R² and R^(2′) taken together with the carbon atom to which they areboth attached form an unsubstituted or substituted carbocyclic ring;

X is

wherein R^(x) is H or one or more substituents independently selectedfrom alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy,alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy,carboxyl, carbamoyl, formyl, alkylamino, dialkylamino,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl,alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy,alkylsulfonylamino, mercapto, and alkylthio;

Z is S, O, SO, SO₂, CHF, CH₂, CF₂, C(═O), or CH(R^(Z)), where R^(Z) is aC₁-C₆ aliphatic group or a carbocyclic or heterocyclic group;

R³ is H or a C₁-C₆ aliphatic group;

R⁴ and R⁵ are independently selected from H, halo, or a C₁-C₆ aliphaticgroup;

R⁶ and R⁷ are independently selected from H, halo or a C₁-C₆ aliphaticgroup;

wherein any of said aliphatic groups are saturated, partially saturatedor fully unsaturated and unsubstituted or substituted by one or moresuitable substituents; and

wherein any of said carbocyclic or heterocyclic groups are unsubstitutedor substituted by one or more suitable substituents; saturated,partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

More specific examples of the compounds of Formula I-B′ comprisecompounds wherein

R¹ is a carbocyclic group,

R² is a C₁-C₆ aliphatic group or a carbocyclic-C₁-C₆-aliphatic group;

Z is S, O, CH₂, CF₂;

R³, R⁴ and R⁵ are each H; and

R⁶ and R⁷ are each a C₁-C₆ aliphatic group;

where any of said aliphatic groups are saturated, partially unsaturatedor fully unsaturated and unsubstituted or substituted by one or moresuitable substituents; and

where any of said carbocyclic or heterocyclic groups are unsubstitutedor substituted by one or more suitable substituents; saturated,partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

Specific examples of the compounds of Formula I-B′ comprise compoundswherein

R¹ is a phenyl group, unsubstituted or substituted with one or moresubstituents selected from alkyl, hydroxyl, halo, halo alkyl,haloalkoxy, methylene dioxy, and di-fluoromethylene dioxy;

R² is an alkenyl group, an aralkyl group or a straight or branched chainsaturated alkyl;

X is

where R^(x) is H;

Z is S;

R³, R⁴ and R⁵ are each H; and

R⁶ and R⁷ are each methyl;

wherein any of said alkenyl, aralkyl, or alkyl groups are unsubstitutedor substituted with one or more substituents, independently selectedfrom methyl, halo, trifluoromethyl or methoxy.

Another specific emobdiment of the compounds of Formula I-B′ comprisecompounds wherein

R¹ is a phenyl group, unsubstituted or substituted with one or moresubstituents selected from alkyl, hydroxyl, halo, halo alkyl,haloalkoxy, methylene dioxy, and di-fluoromethylene dioxy;

R² is an alkenyl group, an aralkyl group or a straight or branched chainsaturated alkyl;

X is

where R^(x) is H;

Z is CF₂;

R³, R⁴ and R⁵ are each H; and

R⁶ and R⁷ are each methyl;

Wherein any of said alkenyl, aralkyl, or alkyl groups are unsbstitutedor substituted with one or more substitutents, independently selectedfrom methyl, halo, trifluoromethyl or methoxy.

Other specific exarnples of this invention, comprise the compoundshaving the Formula I-C:

wherein

R¹ is an aliphatic, carbocyclic or heterocyclic group, or a group havingthe formula: OR^(1′), wherein R^(1′) is a carbocyclic or heterocyclicgroup;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

W is N;

R^(2′) is H or a C₁-C₆ alkyl group;

X is

wherein R^(x) is H; dialkylaminocarbonyl, alkylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl,alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy,alkylsulfonylamino, mercapto, or alkylthio;

Z is CF₂, CH(OH) or C(═O);

R³, R⁴ and R⁵ are each H; and

R⁶ and R⁷ are each methyl.

More specific examples of this invention, comprise the compounds havingthe Formula I-C′, wherein:

R¹ is an aryl group, an aryloxyalkyl group, an alkynyloxy group, aheterocycloalkyloxy group or heteroaryl group;

R² is an alkyl, alkenyl, or alkynyl group, an arylalkyl group; aheteroarylalkyl group, an indanyl group, a chromanyl group, atetrahydronaphthalene group, an aliphatic group, a carbocyclic group, acarbocyclic-aliphatic group, a heterocyclic group, or aheterocyclic-aliphatic group; and

R^(2′) is H;

wherein the alkyl, alkenyl, alkynyl, arylalkyl; heteroarylalkyl,indanyl, chromanyl or tetrahydronaphthalene group is optionaalyunsubstituted or substitutee with one or more substituents independentlyselected from alkyl, hydroxy, halo, haloalkyl, cyano, alkoxy ormethylenedioxy.

Specific examples of this invention, comprise the compounds having theFormula I-C′, wherein:

R¹ is a phenyl group, a phenyoxymethyl group, a tetrahydrofuranyloxygroup, a C₁-C₄ alkynyloxy group, or a isoxazolyl group, where the phenylgroup, phenyoxymethyl group or isoxazolyl group is unsubstituted orsubstituted by hydroxyl or methyl;

R² is an C₁-C₅ alkyl, C₁-C₆ alkenyl, or C₁-C₄ alkynyl group, a benzylgroup; a furanylmethyl group, a thienylmehtyl group, an indanyl group, achromanyl group, a tetrahydronaphthalene group, or a cyclohexenyl group,where the alkyl groups is unsubstituted or substituted with one or morehalogen; and the phenyl group is unsubstituted or substituted withhalogen, hydroxyl, methoxy, methylenedioxy or methyl;

R^(2′) is H;

X is

wherein R^(x) is H; and

Z is CF₂;

Other specific embodiments of this invention comprise the compoundsdepicted by the Formula I-D′ or I-E′, as follows:

wherein

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

W is N;

R^(2′) H or a C₁-C₆ alkyl group;

X is

wherein R^(x) is H or one or more substituents independently selectedfrom alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy,alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy,carboxyl, carbamoyl, formyl, alkylamino, dialkylamino,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl,alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy,alkylsulfonylamino, mercapto, and alkylthio;

Z is O, CH₂, CHF, CF₂, or CH(R^(Z)), where R^(Z) is a C₁-C₆ aliphaticgroup;

R³, R⁴, R⁵, R⁶ and R⁷ are each H; and

wherein any of said aliphatic groups are saturated, partiallyunsaturated or fully unsaturated and unsubstituted or substituted by oneor more suitable substituents; and

wherein any of said carbocyclic or heterocyclic groups are unsubstitutedor substituted by one or more suitable substituents; saturated,partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

More specifically, embodiments of this invention, comprise compoundsaccording to Formula I-D′ or I-E′ wherein

R¹ is a carbocyclic group;

R² is an arylalkyl group;

R^(2′) is H;

X is wherein R^(x) is H; and

Z is CH₂;

wherein said carbocyclic group and arylalkyl group are unsubstituted orsubstituted with one or more substituents selected from methyl, halo, orhydroxy.

Another specific embodiment of this invention comprises compounds ofFormula I-F′, as follows:

wherein

R¹ is a carbocyclic or heterocyclic group,

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

W is N;

R^(2′) is H or a C₁-C₆ alkyl group;

X is

wherein R^(x) is H or one or more substituents independently selectedfrom alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy,alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy,carboxyl, carbamoyl, formyl, alkylamino, dialkylamino,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl,alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy,alkylsulfonylamino, mercapto, and alkylthio;

n is 1 or 2;

R³, R⁴ and R⁵ are each H; and

R⁷ is H;

wherein any of said aliphatic groups are saturated, partiallyunsaturated or fully unsaturated and unsubstituted or substituted by oneor more suitable substituents; and

wherein any of said carbocyclic or heterocyclic groups are unsubstitutedor substituted by one or more suitable substituents; saturated,partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

More specifically, embodiments of this invention, comprise compoundsaccording to Formula I-F′, wherein

R¹ is a carbocyclic group;

R² is an arylalkyl group;

R^(2′) is H;

X is

wherein R^(x) is H;

wherein said carbocyclic group, and arylalkyl group unsubstituted orsubstituted with one or more substituents selected from methyl, halo, orhydroxy.

In one embodiment, the compounds of Formula I-A of this invention,wherein R⁶ and R⁷, taken together with the atom to which they are bound,form a carbocyclic group, comprise spiro-fused bi-cyclic compoundshaving the Formula I-G′:

wherein

R¹ is a carbocyclic or heterocyclic group;

R² is an aliphatic group, a carbocyclic group, a carbocyclic-aliphaticgroup, a heterocyclic group, or a heterocyclic-aliphatic group;

W is N, C or CH;

R^(2′) is H;

X is

wherein R^(x) is H or one or more suitable substituents independentlyselected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl,alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl,alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,diaikylaminbthiocarbonyl, alkylsulfonyl, alkylsulfenyl,alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy,alkylsulfonylamino, mercapto, and alkylthio;

Z is S, O, CH₂, CHF, CF₂, or CH(R^(Z)), where R^(Z) is a C₁-C₆ aliphaticgroup;

n is 2,3 or 4;

R³, R⁴ and R⁵ are each H;

wherein any of said aliphatic groups are saturated, partiallyunsaturated or fully unsaturated and unsubstituted or substituted by oneor more suitable substituents; and

wherein any of said carbocyclic or heterocyclic groups are unsubstitutedor substituted by one or more suitable substituents; saturated,partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

More specific embodiments comprise the compounds of Formula I-G′wherein:

R¹ is-a carbocyclic group;

R² is an arylalkyl group;

W is N;

R^(2′) is H;

X is

wherein R^(x) is H; and

Z is CH₂;

R³, R⁴, R⁵ and R⁷ are each H;

wherein said carbocyclic group and arylalkyl group unsubstituted orsubstituted with one or more substituents selected from methyl, halo, orhydroxy.

More specific embodiments comprise the compounds of Formula I-G′wherein:

R¹ is a carbocyclic group;

R² is an arylalkyl group;

W is N;

R^(2′) is H;

X is

wherein R^(x) is H; and

Z is CF₂;

R³, R⁴, R⁵ and R⁷ are each H;

wherein said carbocyclic group and arylalkyl group unsubstituted orsubstituted with one or more substituents selected from methyl, halo, orhydroxy.

More specific embodiments comprise the compounds of Formula I-G′wherein:

R¹ is a carbocyclic group;

R² is an arylalkyl group;

W is N;

R^(2′) is H;

X is

wherein R^(x) is H; and

Z is S;

R³, R⁴, R⁵ and R⁷ are each H;

wherein said carbocyclic group and arylalkyl group unsubstituted orsubstituted with one or more substituents selected from methyl, halo, orhydroxy.

If an inventive compound is a base, a desired salt may be prepared byany suitable method known in the art, including treatment of the freebase with an inorganic acid, such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acidor galacturonic acid, alpha-hydroxy acid, such as citric acid ortartaric acid, amino acid, such as aspartic acid or glutamic acid,aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If an inventive compound is an acid, a desired salt may be prepared byany suitable method known to the art, including treatment of the freeacid with an inorganic or organic base, such as an amine (primary,secondary, or tertiary); an alkali metal or alkaline earth metalhydroxide; or the like. Illustrative examples of suitable salts includeorganic salts derived from amino acids such as glycine and arginine;ammonia; primary, secondary, and tertiary amines; and cyclic amines,such as piperidine, morpholine, and piperazine; as well as inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum, and lithium.

All compounds of this invention contain at least one chiral center andmay exist as single stereoisomers (e.g., single enantiomers or singlediastereomers), any mixture of stereosisomers (e.g., any mixture ofenantiomers or diastereomers) or racemic mixtures thereof. All suchsingle stereoisomers, mixtures and racemates are intended to beencompassed within the broad scope of the present invention. Compoundsidentified herein as single stereoisomers are meant to describecompounds that are present in a form that contains at least 90% of asingle stereoisomer of each chiral center present in the compounds.Where the stereochemistry of the chiral carbons present in the chemicalstructures illustrated herein is not specified, the chemical structureis intended to encompass compounds containing either stereoisomer ofeach chiral center present in the compound. Preferably, however, theinventive compounds are used in optically pure, that is,stereoisomerically pure, form or substantially optically pure(substantially stereoisomerically pure) form. As used herein, the term“stereoisomeric” purity (or “optical” purity) refers to the“enantiomeric” purity and/or “diastereomeric” purity of a compound.Compounds that are substantially enantiomerically pure contain at least90% of a single isomer and preferably contain at least 95% of a singleisomer of each chiral center present in the enantiomer. Compounds thatare substantially diastereomerically pure contain at least 90% of asingle isomer of each chiral center present in the diastereomer, andpreferably contain at least 95% of a single isomer of each chiralcenter. More preferably, the substantially enantiomerically anddiasteriomerically pure compounds in this invention contain at least97.5% of a single isomer and most preferably contain at least 99% of asingle isomer of each chiral center in the compound. The term “racemic”or “racemic mixture” refers to a mixture of equal amounts ofenantiomeric compounds, which encompasses mixtures of enantiomers andmixtures of enantiomeric diastereomers. The compounds of this inventionmay be obtained in stereoisomerically pure (i.e., enantiomericallyand/or diastereomerically pure) or substantially stereoisomerically pure(i.e., substantially enantiomerically and/or diastereomerically pure)form. Such compounds may be obtained synthetically, according to theprocedures described herein using optically pure or substantiallyoptically pure materials. Alternatively, these compounds may be obtainedby resolution/separation of a mixture of stereoisomers, includingracemic mixtures, using conventional procedures. Exemplary methods thatmay be useful for the resolution/separation of stereoisomeric mixturesinclude chromatography and crystallization/re-crystallization. Otheruseful methods may be found in “Enantiomers, Racemates, andResolutions,” J. Jacques et al., 1981, John Wiley and Sons, New York,N.Y., the disclosure of which is incorporated herein by reference.Preferred stereoisomers of the compounds of this invention are describedherein.

Especially preferred embodiments of this invention comprise compounds,wherein the stereogenic centers (chiral carbons) have the followingdesignated stereochemistry:

More preferably, at least two of the stereogenic centers have thefollowing designated stereochemistry:

Even more preferably, at least three of the stereogenic centers have thefollowing designated stereochemistry:

Exemplary compounds of this invention may be represented as follows:

wherein each of the formula variables are as defined above.

Exemplary compounds of this invention include the following. Theabbreviation “Bn” in some of the following structures indicates a“benzyl” substituent.

and the prodrugs, pharmaceutically active metabolites, andpharmaceutically acceptable salts and solvates thereof.

The invention is also directed to the intermediates of Formula II, whichare useful in the synthesis of certain compounds of Formula I:

The HIV protease inhibitor compounds of this invention include prodrugs,the pharmaceutically active metabolites, and the pharmaceuticallyacceptable salts and solvates thereof. In preferred embodiments, thecompounds of Formula I, prodrugs, pharmaceutically acceptable salts, andpharmaceutically active metabolites and solvates thereof demonstrate anHIV-protease inhibitory activity, corresponding to K_(i) of at least 100nM, an EC₅₀ of at least 10 mM or an IC₅₀ of at least 10 mM. Preferably,the compounds of this invention demonstrate an HIV-protease inhibitoryactivity, corresponding to a K_(i) of at least 10 nM, an EC₅₀ of atleast 1 mM or an IC₅₀ of at least 1 mM. More preferably, the compoundsof this invention demonstrate an HIV-protease inhibitory activityagainst mutant strains of HIV, corresponding to a K_(i) of at least 100nM, an EC₅₀ of at least 10 mM or an IC₅₀ of at least 10 mM. Even morepreferably, the compounds of this invention demonstrate proteaseinhibitory activity against mutant strains corresponding to a K_(i) ofat least 10 nM, an EC₅₀ of at least 1 mM or an IC₅₀ of at least 1 mM.

A “prodrug” is intended to mean a compound that is converted underphysiological conditions or by solvolysis or metabolically to aspecified compound that is pharmaceutically active. A prodrug may be aderivative of one of the compounds of this invention that contains amoiety, such as for example —CO₂R, —PO(OR)₂ or —C═NR, that may becleaved under physiological conditions or by solvolysis. Any suitable Rsubstituent may be used that provides a pharmaceutically acceptablesolvolysis or cleavage product. A prodrug containing such a moiety maybe prepared according to conventional procedures by treatment of acompound of this invention containing, for example, an arnido,carboxylic acid, or hydroxyl moiety with a suitable reagent. A“pharmaceutically active metabolite” is intended to mean apharmacologically active compound produced through metabolism in thebody of a specified compound. Prodrugs and active metabolites ofcompounds of this invention of the above-described Formulas may bedetermined using techniques known in the art, for example, throughmetabolic studies. See, e.g., “Design of Prodrugs,” (Bundgaard, ed.),1985, Elsevier Publishers B.V., Amsterdam, The Netherlands. Thefollowing are examples of prodrugs that can be converted to thecompounds of this invention under physiological conditions, bysolvolysis or metabolically:

A “pharmaceutically acceptable salt” is intended to mean a salt thatretains the biological effectiveness of the free acids and bases of aspecified compound and that is not biologically or otherwiseundesirable. Examples of pharmaceutically acceptable salts includesulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methane-sulfonates (mesylates), propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. A“solvate” is intended to mean a pharmaceutically acceptable solvate formof a specified compound that retains the biological effectiveness ofsuch compound. Examples of solvates include compounds of the inventionin combination with water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, or ethanolamine. In the case of compounds, salts,or solvates that are solids, it is understood by those skilled in theart that the inventive compounds, salts, and solvates may exist indifferent crystal forms, all of which are intended to be within thescope of the present invention and specified formulas.

The present invention is also directed to a method of inhibiting HIVprotease activity, comprising contacting the protease with an effectiveamount of a compound of Formula I, or a pharmaceutically acceptablesalt, prodrug, pharmaceutically active metabolite, or solvate thereof.For example, HIV protease activity may be inhibited in mammalian tissueby administering a compound of Formula I or a pharmaceuticallyacceptable salt, prodrug, pharmaceutically active metabolite, or solvatethereof. More preferably, the present method is directed at inhibitingHIV-protease activity. “Treating” or “treatment” is intended to mean atleast the mitigation of a disease condition in a mammal, such as ahuman, that is alleviated by the inhibition of the activity of HIVproteases. The methods of treatment for mitigation of a diseasecondition include the use of the compounds in this invention in anyconventionally acceptable manner, for example, as a prophylactic. Theactivity of the inventive compounds as inhibitors of HIV proteaseactivity may be measured by any of the suitable methods known to thoseskilled in the art, including in vivo and in vitro assays. Examples ofsuitable assays for activity measurements are escribed herein.Administration of the compounds of the Formula I and theirpharmaceutically acceptable prodrugs, salts, active metabolites, andsolvates may be performed according to any of the generally acceptedmodes of administration available to those skilled in the art.Illustrative examples of suitable modes of administration include oral,nasal, parenteral, topical, transdermal, and rectal.

An inventive compound of Formula I or a pharmaceutically acceptablesalt, prodrug, active metabolite, or solvate thereof may be administeredas a pharmaceutical composition in any pharmaceutical form recognizableto the skilled artisan as being suitable. Suitable pharmaceutical formsinclude solid, semisolid, liquid, or lyophilized formulations, such astablets, powders, capsules, suppositories, suspensions, liposomes, andaerosols. Pharmaceutical compositions of the invention may also includesuitable excipients, diluents, vehicles, and carriers, as well as otherpharmaceutically active agents, depending upon the intended use or modeof administration. Acceptable methods of preparing suitablepharmaceutical forms of the pharmaceutical compositions may be routinelydetermined by those skilled in the art. For example, pharmaceuticalpreparations may be prepared following conventional techniques of thepharmaceutical chemist involving steps such as mixing, granulating, andcompressing when necessary for tablet forms, or mixing, filling, anddissolving the ingredients as appropriate, to give the desired productsfor oral, parenteral, topical, intravaginal, intranasal, intrabronchial,intraocular, intraaural, and/or rectal administration.

The present invention includes pharmaceutical compositions useful forinhibiting HIV protease, comprising an effective amount of a compound ofthis invention, and a pharmaceutically acceptable carrier.Pharmaceutical compositions useful for treating infection by HIV, or fortreating AIDS or ARC, are also encompassed by the present invention, aswell as a method of inhibiting HIV protease, and a method of treatinginfection by HIV, or of treating AIDS or ARC. Additionally, the presentinvention is directed to a pharmaceutical composition comprising atherapeutically effective amount of a compound of the present inventionin combination with a therapeutically effective amount of an HIVinfection/AIDS treatment agent selected from:

-   -   1) an HIV/AIDS antiviral agent,    -   2) an anti-infective agent, and    -   3) an immunomodulator.

The present invention also includes the use of a compound of the presentinvention as described above in the preparation of a medicament for (a)inhibiting HIV protease, (b) preventing or treating infection by HIV, or(c) treating AIDS or ARC.

The present invention further includes the use of any of the HIVprotease inhibiting compounds of the present invention as describedabove in combination with one or more HIV infection/AIDS treatmentagents selected from an HIV/AIDS antiviral agent, an anti-infectiveagent, and an immunomodulator for the manufacture of a medicament for(a) inhibiting HIV protease, (b) preventing or treating infection byHIV, or (c) treating AIDS or ARC, said medicament comprising aneffective amount of the HIV protease inhibitor compound and an effectiveamount of the one or more treatment agents.

Solid or liquid pharmaceutically acceptable carriers, diluents,vehicles, or excipients may be employed in the pharmaceuticalcompositions. Illustrative solid carriers include starch, lactose,calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin,acacia, magnesium stearate, and stearic acid. Illustrative liquidcarriers include syrup, peanut oil, olive oil, saline solution, andwater. The carrier or diluent may include a suitable prolonged-releasematerial, such as glyceryl monostearate or glyceryl distearate, alone orwith a wax. When a liquid carrier is used, the preparation may be in theform of a syrup, elixir, emulsion, soft gelatin capsule, sterileinjectable liquid (e.g., solution), or a nonaqueous or aqueous liquidsuspension. A dose of the pharmaceutical composition contains at least atherapeutically effective amount of the active compound (i.e., acompound of Formula I or a pharmaceutically acceptable salt, prodrug,active metabolite, or solvate thereof), and preferably is made up of oneor more pharmaceutical dosage units. The selected dose may beadministered to a mammal, for example, a human patient, in need oftreatment mediated by inhibition of HIV protease activity, by any knownor suitable method of administering the dose, including: topically, forexample, as an ointment or cream; orally; rectally, for example, as asuppository; parenterally by injection; or continuously by intravaginal,intranasal, intrabronchial, intraaural, or intraocular infusion. A“therapeutically effective amount” is intended to mean the amount of aninventive agent that, when administered to a mammal in need thereof, issufficient to effect treatment for disease conditions alleviated by theinhibition of the activity of one or more variant of the HIV protease.The amount of a given compound of the invention that will betherapeutically effective will vary depending upon factors such as theparticular compound, the disease condition and the severity thereof, theidentity of the mammal in need thereof, which amount may be routinelydetermined by artisans.

The compounds of this invention are also useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants thatare excellent screening tools for more powerful antiviral compounds.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other antivirals to HIV protease,e.g., by competitive inhibition. Thus the compounds of this inventionare commercial products to be sold for these purposes.

General Synthetic Methods

Preferably, the inventive compounds are prepared by the methods of thepresent invention, including the General Methods shown below. Whenstereochemistry is not specified in chemical structures, eitherstereocenter may be utilized. The following abbreviations also apply:Boc (tert-butoxycarbonyl), Ac (acetyl), Cbz (benzyloxycarbonyl), DMB(2,4-dimethoxybenzyl), TBS (tert-butyldimethylsilyl), TBDPS(tert-butyldiphenylsilyl), Ms (methanesulfonate), Ts (toluenesulfonate),Bn (benzyl), and Tr (triphenylmethyl)

All reactions were performed in septum-sealed flasks under a slightpositive pressure of argon unless otherwise noted. All commercialreagents and solvents were used as received from their respectivesuppliers with the following exceptions: Tetrahydrofuran (THF) wasdistilled from sodium benzophenone ketyl prior to use. Dichloromethane(CH₂Cl₂) was distilled from calcium hydride prior to use. Flashchromatography was performed using silica gel 60 (Merck art. 9385). ¹HNMR spectra were recorded at 300 MHz utilizing a Varian UNITYplus 300spectrometer. Chemical shifts are reported in ppm (δ) downfield relativeto internal tetramethylsilane, and coupling constants are given inHertz. Infrared absorption spectra were recorded using a Perkin-Elmer1600 series FTIR spectrometer. Elemental analyses were performed byAtlantic Microlab, Inc., Norcross, Ga. Melting points are uncorrected.

All P2′ amine variants mentioned in General Methods A-E describedhereinbelow were either purchased and used directly or synthesized asfollows.Method A: Representative Procedure for Reduction of Ketones to Alcohols.

6,7-Dihydro-4-(5H)-benzofuranone (1) (1.00 g 7.34 mmol) was dissolved inmethanol (55 mL). The mixture was cooled to 0° C. and NaBH₄ (0.31 g,8.08 mmol) was added in portions. The reaction was stirred for 2 h at 0°C. at which time the methanol was evaporated. The residue was dissolvedin EtOAc and poured into NaHCO₃ (saturated aqueous) and extracted withEtOAc (3×10 mL). The combined organic extracts were washed with brine(10 mL), passed over a short plug of Na₂SO₄, and concentrated in vacuoto give 2 (1.01 g, 99%, as a mixture of isomers) as a pale yellow, thickoil, which was of sufficient quality to be advanced to the next stepwithout further purification. Rf (50% EtOAc/hexanes): 0.53.Method B: Representative Procedure for Reduction of Acids to Alcohols.

Tiglic acid (1) (20.0 g, 0.200 mol) was dissolved in ether (80 ml) andadded dropwise over 30 min to a suspension of LiAlH₄ (15.0 g, 0.417 mol)in ether (80 ml) at 0° C. and the reaction mixture was allowed to warmto room temperature. After 3 h the mixture was re-cooled to 0° C. andquenched slowly by the addition of H₂O (15 ml), 15% NaOH (15 ml) and H₂O(15 ml). The reaction mixture was filtered to remove the granularprecipitate and washed thoroughly with ether. The filtrate was washedsuccessively with 1N HCl, NaHCO₃ (saturated aqueous), and brine. Thecombined organic layers were dried over MgSO₄ and concentrated in vacuoto give (E)-2-methyl-but-2-en-1-ol (2) as a clear oil (12.8 g, 74%).Method C: Representative Procedure for Alkylation of Phenols Alcohols.

3-Hydroxybenzylalcohol (1) (0.500 g 4.03 mmol) was dissolved in DMF (2mL) at ambient temperature. Ethyl bromide (0.900 mL, 12.1 mmol) andfinely crushed K₂CO₃ (2.78 g, 20.1 mmol) were added and the reactionmixture was stirred for 5 h. The DMF was then removed in vacuo and theresidue was partitioned between EtOAc and H₂O, and extracted with EtOAc(3×10 mL). The organic layers were washed with brine (10 mL) and passedover a short plug of Na₂SO₄. The solvents were removed in vacuo to givealcohol 2 (0.55 g, 90%) as a pale yellow, thick oil, which was ofsufficient quality to be advanced to the next step without furtherpurification. Rf (40% EtOAC/hexanes): 0.69.Method D: Representative Procedure for Conversion of Alcohols to Amines.

3-Ethoxy-phenyl-methanol (1) (1.23 g 8.08 mmol) was dissolved in CH₂Cl₂(10 mL) at ambient temperature and diphenylphosphoryl azide (2.67 g,9.70 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.45 mL, 9.70 mmol)were added. The mixture was stirred for 5 h at which time the CH₂Cl₂ wasremoved in vacuo and the crude residue was partitioned between EtOAc andH₂O and extracted with EtOAc (3×10 mL). The combined organic layers werewashed with brine (10 mL), passed over a short plug of Na₂SO₄, andconcentrated in vacuo to give a yellow oil that was loaded directly ontoa flash silica gel column and was quickly eluted with 10% EtOAc/hexanes.The solvents were removed in vacuo to give azide 2 (1.43 g, 84%) as acolorless oil. Rf (30% EtOAc/hexanes): 0.79.

1-Azidomethyl-3-ethoxy-benzene (2) (1.19 g 6.71 mmol) was dissolved inMeOH (15 mL) and palladium 10% on activated carbon, wet (20% in weight)was added. The reaction was hydrogenated for 30 min at 40 PSI in a ParrHydrogenator. The black suspension was then filtered through compactedcelite and the methanol was removed in vacuo to give amine 3 (0.88 g,88%) as a pale yellow, thick oil, which was of sufficient quality to beadvanced to the coupling reactions without further purification.Method E: Representative Procedure for Conversion of Alcohols toBromides.

Cis-2-penten-1-ol (1) (1.00 g, 11.6 mmol) and carbon tetrabromide (3.85g, 13.9 mmol) were dissolved in CH₂Cl₂ (75 mL). The mixture was cooledto 0° C. and triphenylphosphine (3.65 mL, 13.9 mmol) dissolved in CH₂Cl₂(50 mL) was added dropwise. The mixture was allowed to warm to roomtemperature and was stirred overnight. The CH₂Cl₂ was removed in vacuoand the crude residue was loaded directly onto a flash silica gel columnand eluted quickly with 20% EtOAc/hexanes. The solvents were removed invacuo to give bromide 2 (1.53 g, 88%) as a colorless volatile oil. Rf(30% EtOAC/hexanes): 0.89.Method F: Representative Procedure for Conversion of Bromides to Amines.

A mixture of bromide 1 (3.00 g, 20.1 mmol),di-tert-butyl-iminodicarboxylate (4.8 g, 22 mmol), and K₂CO₃ (3.10 g,80.4 mmol) in DMF (30 ml) was stirred at ambient temperature overnight.The mixture was partitioned between 1N HCl and EtOAc. The organic layerwas washed with H₂O and brine, then dried over NaSO₄. Concentration invacuo affored a yellow oil which upon purification by flash columnchromatography (hexanes to 5% EtOAc/Hexane gradient) yielded protectedamine 2 as a clear oil (2.0 g, 35%).

A mixture of the diBOC amine 2 (2.0 g, 7.0 mmol), trifluoroacetic acid(2.7 ml, 35 mmol) and CH₂Cl₂ (40 ml) was stirred at ambient temperatureovernight. The reaction mixture was concentrated in vacuo to give theTFA salt of (E)-2-methyl-but-2-enylamine (3).Method G: Representative Procedure for Reduction of Aromatic NitroGroups by Hydrogenation.

Compound 1 (2.04, 5.79 mmol) was dissolved in EtOAc (20 mL) andpalladium 10% on activated carbon, wet (20% in weight) was added. Thereaction was hydrogenated for 4 h at 45 PSI in a Parr Hydrogenator. Theblack suspension was then filtered through. compacted celite and themethanol was removed in vacuo to give aniline 2 (1.65 g, 88%) as a paleyellow, thick oil, which was of sufficient quality to be advanced to theacetylation reaction without firther purification.Method H: Representative Procedure for Acetylation of Anilines.

Aniline 1 (1.65 g, 5.12 mmol) was dissolved in CH₂Cl₂ (25 mL) at ambienttemperature. Acetyl chloride (0.48 g, 6.14 mmol) andN,N-Diisopropylethylamine (0.79 g, 6.14 mmol) were added, and thereaction was stirred overnight. The CH₂Cl₂ was removed in vacuo and thecrude residue was partitioned between EtOAc and 5% KHSO₄ and extractedwith EtOAc (3×10 mL). The combined organic extracts were washed withNaHCO₃ (saturated aqueous, 10 mL), brine (10 mL), and dried over Na₂SO₄.The solvents were removed in vacuo to give an orange oil which was ofsufficient quality to be advanced to the next step without furtherpurification. Rf (50% EtOAC/hexanes): 0.42.Method I: Representative Procedure for Reduction of Aldehydes to Amines.

Hydroxyl amine hydrochloride (758 mg, 10.7 mmol) and pyridine (2.16 mL)was added to a solution of 2,2-difluoro-5-formyl benzodioxole (1) (2.00g, 10.7 mmol) in MeOH (10 mL). After 18 hours the MeOH was removed invacuo. The reaction mixture was diluted with EtOAc and was washedsequentially with H₂O, 10% w/v CuSO₄, and brine and then dried overMgSO₄. The solution was concentrated in vacuo. The hydroxy imine waspurified by column chromatography using 20% EtOAc/Hexanes to give 1.37 g(64% yield) of a white solid. Imine was then subjected to LAH reductionas described above to provide amine 3.Method J: Representative Procedure for the Hydroxylation of aSubstituted Benzoic Acid

2,5-dimethyl-benzoic acid (1) (20 g, 133 mmol) was dissolved inconcentrated H₂SO₄ (30 mL) and fuming H₂SO₄ (20% SO₃, 70 mL). Thereaction mixture was heated to 110° C. for 2 hours. After cooling, thesolution was poured carefully into a beaker of ice H₂O (400 mL) and wasthen neutralized with 20% aqueous NaOH (400 mL). The H₂O was partiallyremoved in vacuo until a white salt mixture started to form. The solidwas collected on a sintered-glass funnel and was then dried in a vacuumoven. The dried salt mixture was placed in a ceramic crucible with KOH(160 g) and was melted together using a butane torch for 0.5 h. Aftercooling, the fused solid was dissolved in H₂O (300 mL) and acidifiedwith concentrated HCl (300 mL). The product was extracted from theaqueous solution with EtOAc (3×200 mL). The combined organic layers werewashed with brine (100 mL) and dried over MgSO₄. The solvents wereremoved in vacuo and the solid residue was recrystallized with 20%EtOAc/CHCl₃ four times to afford 3-hydroxy-2,5-dimethyl-benzoic acid (2)as a light brown solid (9.8 g, 44%)

¹H NMR (Acetone-d₆) δ 10.93 (br s, 1H), 8.34 (br s, 1H), 7.20 (s, 1H),6.86 (s, 1H), 2.37 (s, 3H), 2.24 (s, 3H).

-   References—Fujiwara, A. N; Acton, E. M. Can. J. Chem. 1970, 48,    1346-1349.-   Charlesworth, E. H; Levene, L. Can. J. Chem. 1963, 41, 1071-1077.

The following amines were synthesized for the corresponding examplenumbers:

EXAMPLE A35 AND EXAMPLE A36

Amines were generated from reducing the corresponding ketone asdescribed in method A above followed by conversion to the azide andreduction as described in method D above. The mixture of isomers wascoupled to the chiral thiazolidine core and separated.

EXAMPLE A37 AND EXAMPLE A38

Amines were generated as described for Examples A35 and A36, separatingthe diastereomers at the thiazolidine stage.

EXAMPLE A84 AND EXAMPLE A85

Amines were generated as described for Examples A35 and A36, separatingthe diastereomers at the thiazolidine stage.

EXAMPLE A86 AND EXAMPLE A87

Amines were generated as described for Example A35 and A36, separatingthe diastereomers at the thiazolidine stage.

EXAMPLE A43

Amine was generated by alkylation of 3-hydroxybenzyl alcohol with ethylbromide as describe in method C above followed by conversion of thealcohol to the amine as described in method D above provided desiredamine.

EXAMPLE A44

Amine was generated as described above for Example A43 using thecyclopropyl alkylating agent.

EXAMPLE A93

Amine was generated as described above for Example A43 usingpropylbromide as the alkylating agent.

EXAMPLE A67

Amine was generated from displacement of bromide in 3-nitrobenzylbromidewith di BOC amine as described in method F above. Reduction of the nitromoiety to the aniline (method G above) followed by acetylation (method Habove) and BOC removal (method F above) provided desired amine.

EXAMPLE A72, EXAMPLE A73 AND EXAMPLE A80

Amines were generated from conversion of the corresponding primaryalcohols as described in method E above. Displacement of the bromidewith di BOC amine and deprotection with TFA (method F above) providedthe desired amines.

EXAMPLE A77

Amine was generated from 3-dimethylaminobenzyl alcohol as described inmethod D above.

EXAMPLE A48

Amine was generated by bromination of the corresponding methyl compound(Nussbaumer, P., et. al. J. Med. Chem., 1991, 34, 65-73.). Conversion ofthe bromide to the amine was accomplished by azide displacement of thebromide followed by reduction as described in method D above.

EXAMPLE A69

Amine was generated by reduction of the corresponding methyl ester tothe primary alcohol (Wipf, J. Org. Chem. 1994, 59, 4875-86.). Conversionto the bromide (method E above) followed by displacement with diBOCamine and deprotection (method F above) provided desired amine.

EXAMPLE A70 AND EXAMPLE A71

Amines were generated from the corresponding carboxylic acids. Reductionof the acid as described in method B above followed by bromidedisplacement as described in method E above gave the primary bromide.Conversion of the bromide to the primary amine followed the proceduredescribed in method F above.

EXAMPLE A74

Amine was generated from the primary alcohol as described in method Dabove.

EXAMPLE A76

Amine was generated by first reduction of the corresponding aldehydewith sodium borohydride to the primary alcohol (Dondoni, J. Org. Chem.1995, 60, 4749-54.). The alcohol was then converted to the amine asdescribed in method D above.

EXAMPLE A82 AND EXAMPLE A83

Amines were generated by conversion of the primary alcohol as describedin method D above. Tetrahydrofuran amine (Example A83) was the byproductof over-reduction of A82.

EXAMPLE A91

Amine was generated from the corresponding carboxylic acid. Reduction ofthe acid as described in method B above gave the primary alcohol. Thealcohol was then converted to the amine using the procedure described inmethod D above.

EXAMPLE A92

Amine was generated from 3-benzyloxybenzyl alcohol. Conversion to theazide and reduction of both the azide and benzyl protecting group wereaccomplished using method D as described above with longer hydrogenationtime.

EXAMPLE A94

Amine was generated by LiAlH₄ reduction of 2-cyanophenol (Ludeman, S.M., et. al. J. Med. Chem. 1975, 18, 1252-3.).

EXAMPLE A88 AND EXAMPLE A89

Amines were generated from the corresponding achiral ketone prepared bythe method of Haunz (Huanz, et. al. Synth. Commun. 1998, 28,1197-1200.). The ketone was reduced to the alcohol as a mixture ofisomers using method A as described above. The mixture was converted toa mixture of amines by the procedure described in method D above. Theamines were coupled to the thiazolidine core as a mixture and were thenseparated to provide Examples A88 and A89.

EXAMPLE A78 AND EXAMPLE A79

Amines were generated from the corresponding achiral ketone prepared bythe method of Bell (Bell, et. al. J. Med. Chem. 1998, 41, 2146-63.). Theketone was reduced to the alcohol as a mixture of isomers using method Aas described above. The mixture was converted to a mixture of amines bythe procedure described in method D above. The amines were coupled tothe thiazolidine core as a mixture and were then separated to provideExamples A78 and A 79.

EXAMPLE A81

Amine was generated from the corresponding carboxylic acid. Reduction ofthe acid using the procedure described in method A above provided theprimary alcohol which was converted to the bromide using the method ofOnda (Onda, M. et. al. Chem. Pharm. Bull. 1971, 10, 2013-19.). Thebromide was then converted to the amine using the procedure described inmethod F above.

EXAMPLE A110

Amine was generated from the condensation of o-tolualdehyde with2-aminoethanol followed by reduction with sodium borohydride(Tetrahedron Assym. 1997, 8, 2367-74.).

EXAMPLE A103

Amine was generated from the corresponding aldehyde by the reductiveamination procedure described in method I above.

EXAMPLE A105

Amine was generated by reduction of the corresponding methyl ester tothe primary alcohol (Wipf, J. Org. Chem. 1994, 59, 4875-86.). Thealcohol was converted to the amine by the procedure described in methodD above.

EXAMPLE A107

Amine was generated from reduction of the corresponding carboxylic acidto the primary alcohol as described in method A above. The alcohol wasconverted to the amine using the procedure described in method D above.

EXAMPLE A106 AND EXAMPLE A97

Amines were generated by the borane reduction of the correspondingcarboxylic acids to the primary alcohols. The alcohols were converted tothe amines using the procedure described in method D above.

EXAMPLE A46

Amine was generated by the condensation of ethylacetoacetate withcyanoacetamide followed by reaction with phosphorus oxychloride toprovide 3-cyano-2,5-dihydroxy-4-methylpyridine. Hydrogenation withpalladium dichloride gave the 3-cyano-4-methylpyridine which washydrogenated with Raney nickel in ammonia and ethanol to afford thedesired amine (J. Org. Chem. 1959, 25, 560.).

EXAMPLE A10

Amine was generated by a reductive amination with the correspondingaldehyde (Arch. Pharm. 1987, 320, 647-54.).

EXAMPLE A109

Amine was generated on the thiazolidine core as follows:

Diphenylchlorophosphate (1.0 ml, 4.2 mmol) followed by triethylamine(0.59 ml, 4.2 mmol) were added to a cooled 0° C. solution of BOC-DMTA 1(1.0 g, 3.8 mmol) in EtOAc (10 ml). The mixture was stirred for 1 h andat which time triethylamine (0.59 ml, 4.2 mmol) and ethanolamine (0.25ml, 4.2 mmol) were added. The reaction was left to stir overnight atambient temperature and then partitioned between 1N HCl and EtOAc. Theorganic layer was washed with NaHCO₃ (saturated aqueous) and brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to a paleyellow oil 2. The oil was stirred with thionyl chloride (2 ml) for 45min at room temperature. The mixture was concentrated in vacuo and theresidual oil was partitioned between 1N NaOH and EtOAc. The organiclayer was extracted with 1N HCl (2×20 ml). The combined aqueous layerswere made basic with 1N NaOH and then extracted with EtOAc (3×60 ml).The organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give (R)-5,5-Dimethyl-thiazolidine-4-carboxylicacid (2-chloro-ethyl)-amide 3 as a clear oil (0.39 g, 55%).

The following amines were prepared as described:

EXAMPLE A65

EXAMPLE A66

EXAMPLE A75

The above amines were prepared according to Carlsen, H. J., J.Heterocycle Chem. 1997, 34, 797-806.

EXAMPLE A90

The above amine was prepared according to O'Brien, P. M., J. Med. Chem.1994, 37, 1810-1822.

EXAMPLE A10

The above amine was prepared according to Weinheim, G. Arch. Pharm.1987, 320, 647-654.

The synthesis of compounds with the general structure 5 is as follows.The boc-protected thiazolidine carboxylic acid 1 is coupled to therequisite amines 2 to yield amino amides 3 using a two step process. Theprocess includes treatment of 1 with 2 in the presence of eitherdiphenylchlorophosphate or HATU, followed by exposure to methanesulfonic acid. Final compounds 5 are obtained by a DCC-mediated couplingof 3 and 4 followed by deprotection of the P2 phenol. Final compoundswere purified either by flash chromatography or preparative HPLC.

An alternative approach to the general structure 5 is as follows. Thethiazolidine ester 6 is coupled to acid 7 under carbodiimide reactionconditions, resulting in product 8 which is converted to acid 9 by mildbase hydrolysis. Acid 9 is combined with various amines, usingdiphenylphosphoryl azide, followed by cleavage of the P2 acetate toyield final compounds 5. The products were purified by either flashchromatography or preparative HPLC.

Specific Method A EXAMPLE A13-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (1,2,3,4-tetrahydro-naphthalen -1-yl)-amide

The title compound was prepared as follows.(R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1(0.3 g, 1.15 mmol) was dissolved in EtOAc (3 mL) and cooled to 0° C.Diphenyl chlorophosphate (0.26 mL, 1.26 mmol) was added followed by TEA(0.18 mL, 1.26 mmol). The reaction was stirred at 0° C. for 1 h, andtreated with (S)-1,2,3,4-Tetrahydro-1-naphthylamine (0.19 g, 1.26 mmol).The reaction mixture was stirred at room temperature overnight, thenpartitioned between 1N HCl (5 mL) and EtOAc (10 mL). The organic layerwas washed with saturated NaHCO₃, brine, dried over Na₂SO₄ andconcentrated to a light yellow oil. The resulting crude oil. wasdissolved in EtOAc (5 mL) and the cooled to 0° C. Methanesulfonic acid(0.36 mL, 5.32 mmol) was added and the solution was stirred at 0° C. for15 minutes, then at room temperature for 1 h. The mixture was re-cooledto 0° C. and quenched with 5% Na₂CO₃ (5 mL) then extracted with EtOAc(10 mL). The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give 3 as a yellow oil. The yellow oil 3 (0.34g, 1.15 mmol) was dissolved in EtOAc (12 mL). AMB-AHPBA 4 (0.40 g, 1.09mmol) was added followed by HOBt (0.15 g, 1.09 mmol). The mixture wasstirred at room temperature 1 h, then cooled to 0° C. DCC (0.24 g, 1.15mmol) was slowly added as solution in EtOAc (6 mL). The mixture waswarmed to room temperature and stirred overnight. The mixture wasfiltered and the filtrate was washed with 1N HCl (10 mL), saturatedNaHCO₃ (10 mL), brine (10 mL), dried over Na₂SO₄ and concentrated togive a crude white solid (contaminated with DCU). The DCU was removed byflash chromatography (30% to 50% EtOAc in hexanes) to provide a whitesolid, which was dissolved in MeOH (2 mL) and treated with 4N HCl in1,4-dioxane (0.26 mL, 1.1 mmol). The reaction was stirred at roomtemperature overnight then partitioned between 1N HCl (10 mL) and EtOAc(10 mL). The organic layer was washed with saturated NaHCO₃, dried overNa₂SO₄ and concentrated to a residue which was purified by flashchromatography (60% EtOAc in hexanes) to provide the title compound as awhite solid: mp=125-126° C.; IR (cm⁻¹) 3320, 2932, 1704, 1644, 1530,1454, 1361, 1284; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.28 (d, J=8.6, 1H),8.21 (d, J=8.8, 1H), 7.35-6.91 (m, 10H), 6.76 (d, J=8.0, 1H), 6.54 (d,J=7.5, 1H), 5.34 (d, J=6.0, 1H), 5.13 (d, J=9.0, 1H), 5.02 (d, J=9.0,1H), 4.60-4.30 (m, 4H), 2.81-2.68 (m, 4H), 1.81 (s, 3H), 1.78-1.60 (m,4H), 1.48 (s, 3H), 1.45 (s, 3H); Anal. Calcd for C₃₄H₃₉N₃O₅S.1.5H₂O: C,64.95; H, 6.73; N, 6.68. Found: C, 64.88; H, 6.31; N, 6.18.

EXAMPLE A2(R)-3-((2S,3R)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-methoxy-benzylamide

White solid: mp 108-110° C.; IR (neat, cm⁻¹) 3310, 2965, 1644, 1586,1531, 1455, 1359, 1284; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.40 (t, J=6.0,1H), 8.09 (d, J=8.1, 1H), 7.31-6.52 (m, 12H), 5.49 (d, J=6.0, 1H), 5.12(d, J=9.3, 1H), 5.00 (d, J=9.3, 1H), 4.44-4.35 (m, 3H), 4.42 (s, 1H),4.09 (dd, J=15.0, 6.0, 1H), 3.69 (s, 3H), 2.87-2.67 (m, 2H), 1.82 (s,3H), 1.49 (s, 3H), 1.34 (s, 3H); Anal. Calcd for C₃₂H₃₇N₃O₆S.0.75H₂O: C,63.50; H, 6.41; N, 6.94. Found: C, 63.60; H, 6.23; N, 6.80.

The following examples were prepared by the specific method outlinedabove using the requisite amine 2.

EXAMPLE A3(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (pyridin-2-ylmethyl)-amide

IR (neat cm⁻¹) 3315, 1642, 1529, 1437, 1372, 1284; ¹H NMR (DMSO-d₆) δ9.38 (s, 1H), 8.59 (t, J=5.0, 1H), 8.45 (d, J=4.0, 1H), 8.15 (d, J=8.2,1H), 7.65 (td, J=7.5, 1.8, 1H), 7.39 (d, J=7.9, 1H), 7.29-7.11 (m, 7H),6.93 (t, J=7.7, 1H), 6.77 (d, J=8.1, 1H), 6.54 (d, J=7.0, 1H), 5.51 (d,J=6.6, 1H), 5.15 (d, J=9.2, 1H), 5.03 (d, J=9.2, 1H), 4.50-4.26 (m, 5H),2.87-2.68 (m, 2H), 1.82 (s, 3H), 1.52 (s, 3H), 1.35 (s, 3H); HRMS (ESI)m/z calcd for C₃₀H₃₄N₄O₅SNa (M+Na)⁺ 585.2148, found 585.2141.

EXAMPLE A43-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (1,2,3,4-tetrahydro-naphthalen -1-yl)-amide

White solid: mp=123-125° C.; IR (cm⁻¹) 3314, 2932, 1704, 1644, 1584,1530, 1454, 1360, 1284; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.42 (d, J=8.6,1H), 8.23 (d, J=8.0, 1H), 7.38-6.90 (m, 10H), 6.77 (d, J=8.0, 1H), 6.45(d, J=6.0, 1H), 5.45 (d, J=6.0, 1H), 5.02 (d, J=9.0, 1H), 4.99 (d,J=9.0, 1H), 5.11-4.40 (m, 4H), 2.90-2.69 (m, 4H), 1.81 (s, 3H),1.77-1.58 (m, 4H), 1.49 (s, 3H), 1.42 (s, 3H); Anal. Calcd forC₃₄H₃₉N₃O₅S.1.25H₂O: C, 65.42; H, 6.70; N, 6.73. Found: C, 65.41; H,6.46; N, 6.60.

EXAMPLE A5(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (pyridin-3-ylmethyl)-amide

IR (neat cm⁻¹) 3310, 2931, 1642, 1537, 1455, 1373, 1279; ¹H NMR(DMSO-d₆) δ 9.39 (s, 1H), 8.55-8.50 (m, 2H), 8.38 (s, 1H), 8.15 (d,J=8.2, 1H), 7.68 (d, J=8.1, 1H), 7.30-7.14 (m, 6H), 6.94 (t, J=7.5, 1H),6.77 (d, J=8.1, 1H), 6.54 (d, J=7.7, 1H), 5.51 (d, J=6.6, 1H), 5.14 (d,J=9.2, 1H), 5.03 (d, J=9.2, 1H), 4.49-4.41 (m, 4H), 4.18 (dd, J=15.4,5.5, 1H), 2.85-2.67 (m, 2H), 1.81 (s, 3H), 1.49 (s, 3H), 1.31 (s, 3H);HRMS (ESI) m/z calcd for C₃₀H₃₅N₄O₅S (M+H)⁺ 563.2323, found 563.2337.

EXAMPLE A63-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiiazolidine-4-carboxylicacid methyl-(3-methyl-thiophen-2-ylmethyl)-amide

IR (neat or KBr cm⁻¹) 3150, 3000, 2942, 2187, 1712, 1600, 1567, 1505; ¹HNMR (DMSO-d₆) δ 9.36 (s, 1H), 8.44 (t, J=7.98, 1H), 8.13-8.07 (m, 2H),7.34-7.13 (m, 5H), 6.93 (t, J=7.9, 1H), 6.78 (d, J=7.7, 1H), 6.53 (d,J=7.1, 1H), 5.45 (d, J=7.0, 1H), 5.12 (dd, J=7.8, 8.2 1H), 4.51-4.31 (m,4H), 2.86-2.67 (m, 2H), 2.19 (s, 3H), 1.81 (s, 3H), 1.51 (s, 3H), 1.34(s, 3H); Anal. Calcd for C₃₀H₃₅N₃O₅S₂: calculated C, 61.94, H, 6.06 N,7.22. Found C, 62.38, H, 6.23, N, 7.17.

EXAMPLE A7(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (benzo[b]thiophen-3-ylmethyl)-amide

IR (neat cm⁻¹) 3401, 2931, 1637, 1531, 1455, 1367, 1284, 1108; ¹H NMR(DMSO-d₆) δ 9.39 (s, 1H), 8.52 (t, J=5.7, 1H), 8.17 (d, J=8.2, 1H), 7.93(d, J=6.4, 1H), 7.86 (d, J=6.9, 1H), 7.57 (s, 1H), 7.35-7.11 (m, 7H),6.94 (t, J=7.9, 1H), 6.78 (d, J=7.9, 1H), 6.56 (d, J=7.5, 1H), 5.47 (d,J=5.0, 1H), 5.16 (d, J=9.2, 1H), 5.02 (d, J=9.2, 1H), 4.67 (dd, J=15.2,5.9, 1H), 4.47-4.34 (m, 4H), 2.89-2.70 (m, 2H), 1.83 (s, 3H), 1.49 (s,3H), 1.34 (s, 3H); HRMS (ESI) m/z calcd for C₃₃H₃₅N₃O₅S₂Na (M+Na)⁺640.1910, found 640.1919; Anal. Calcd for C₃₃H₃₅N₃O₅S₂.H₂O: C, 62.34; H,5.87; N, 6.61. Found: C, 62.93; H, 5.80; N, 6.57.

EXAMPLE A8(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (pyridin-4-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.55 (t, J=6.2, 1H), 8.42 (m, 1H), 8.13(d, J=8.2, 1H), 7.30-7.19 (m, 7H), 6.94 (t, J=7.7, 1H), 6.77 (d, J=7.7,1H), 6.54 (d, J=7.1, 1H), 5.54 (d, J=6.8, 1H), 5.15 (d, J=9.1, 1H), 5.02(d, J=9.1, 1H), 4.48-4.13 (m, 5H), 2.87-2.68 (m, 2H), 1.81 (s, 3H), 1.52(s, 3H), 1.35 (s, 3H); HRMS (ESI) m/z calcd for C₃₀H₃₄N₄O₅SNa (M+Na)⁺585.2142, found 585.2153.

EXAMPLE A9(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (2,3-dihydro-benzofuran-5-ylmethyl)-amide

IR (neat, cm⁻¹) 3330, 2919, 1643, 1490, 1443, 1367, 1284, ¹H NMR(DMSO-d₆) δ 9.37 (s, 1H), 8.35 (m, 1H), 8.12 (d, J=7.9, 1H), 7.32-7.09(m, 6H), 6.99-6.91 (m, 2H), 6.77 (d, J=8.1, 1H), 6.68-6.53 (m, 2H), 5.45(d, J=6.2, 1H), 5.12 (d, J=8.8, 1H), 5.00 (d, J=8.9, 1H), 4.50-4.39 (m,6H), 4.29 (dd, J=14.5, 6.2, 1H), 4.14-4.04 (m, 2H), 3.15-2.99 (m, 2H),1.81 (s, 3H), 1.48 (s, 3H), 1.33 (s, 3H); HRMS (ESI) m/z calcd forC₃₃H₃₇N₃O₆SNa (M+Na)⁺ 626.2295, found 626.2283.

EXAMPLE A103-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (3-methyl-pyridin-4-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.47 (t, J=6.0, 1H), 8.29 (m, 2H), 8.11(d, J=8.3, 1H), 7.32-7.14 (m, 6H), 6.94 (t, J=7.7, 1H), 6.78 (dd, J=7.7,1.0, 1H), 6.55 (dd, J=7.7, 1.0, 1H), 5.49 (d, J=6.7, 1H), 5.16 (d,J=9.1, 1H), 5.03 (d, J=9.1, 1H), 4.51-4.38 (m, 3H), 4.49 (s, 1H), 4.13(dd, J=16.4, 5.1, 1H), 2.88-2.69 (m, 2H), 2.25 (s, 3H), 1.83 (s, 3H),1.53 (s, 3H), 1.37 (s, 3H); HRMS (ESI) m/z calcd for C₃₁H₃₇N₄O₅S (M+H)⁺577.2485, found 577.2463; Anal. Calcd for C₃₁H₃₆N₄O₅S.0.3H₂O: C, 63.96;H, 6.34; N, 9.63; S, 5.51. Found: C, 63.95; H, 6.42; N, 9.51; S, 5.22.

EXAMPLE A11(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (naphthalen-1-ylmethyl)-amide

IR (neat, cm⁻¹) 3425, 1643, 1531, 1455, 1378, 1290, 1108, ¹H NMR(DMSO-d₆) δ 9.39 (s, 1H), 8.50 (t, J=5.9, 1H), 8.15 (d, J=8.0, 2H), 8.07(d, J=9.0, 1H), 7.90 (d, J=7.1, 1H), 7.81 (d, J=8.1, 1H), 7.54-7.12 (m,9H), 6.95 (d, J=7.0, 1H), 6.78 (d, J=8.1, 1H), 6.56 (d, J=7.0, 1H), 5.15(d, J=9.2, 1H), 5.01 (d, J=9.2, 1H), 4.95-4.86 (m, 1H), 4.76-4.48 (m,4H), 2.90-2.71 (m, 2H), 1.84 (s, 3H), 1.47 (s, 3H), 1.34 (s, 3H); HRMS(ESI) m/z calcd for C₃₅H₃₇N₃O₅SNa (M+Na)⁺ 634.2346, found 634.2332.

EXAMPLE A12(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid [(R)-1-(tetrahydro-furan-2-yl)methyl]-amide

White solid: mp=105-107° C.; IR (cm⁻¹) 3339, 1644, 1537, 1454, 1372,1285, 1079; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.12 (d, J=8.8, 1H), 8.01(t, J=5.0, 1H), 7.34-7.15 (m, 5H), 6.93 (t, J=7.5, 1H), 6.76 (d, J=7.5,1H), 6.53 (d, J=7.5, 1H), 5.45 (d, J=5.5, 1H), 5.07 (d, J=9.3, 1H), 4.99(d, J=9.3, 1H), 4.50-4.10 (m, 3H), 3.83-3.55 (m, 5H), 3.20-3.00 (m, 2H);2.90-2.60 (m, 2H), 1.90-1.70 (m, 2H), 1.79 (s, 3H), 1.48 (s, 3H), 1.34(s, 3H); Anal. Calcd for C₂₉H₃₇N₃O₆S.0.5H₂O: C, 61.68; H, 6.78; N, 7.44.Found: C, 61.46; H, 6.74; N, 7.47.

EXAMPLE A133-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiiazolidine-4-carboxylicacid cyclohexylmethyl-amide

IR (neat or KBr cm⁻¹) 3743, 2924, 2360, 1868, 1844, 1771, 1699, 1646; ¹HNMR (DMSO-d₆) δ 9.36 (s, 1H), 8.13 (d, J=7.9 1H), 7.85 (t, J=7.2, 1H),7.34-7.13 (m, 5H), 6.93 (t, J=7.9, 1H), 6.78 (d, J=7.7, 1H), 6.53 (d,J=7.1, 1H), 5.15 (d, J=7.0, 1H), 5.08 (d, J=7.8, 1H), 4.81 (s, 1H), 4.51(d, J=6.2, 1H), 4.46 (s, 1H), 4.38 (d, J=6.32, 1H), 4.31 (s, 6H),2.86-2.67 (m, 4H), 2.55 (s, 1H), 1.81 (s, 3H), 1.64-1.54 (m, 6H), 1.51(s, 3H), 1.39 (s, 3H), 1.18-1.08 (m, 4H), 0.99-0.78 (m, 3H); Anal. Calcdfor C₃₂H₄₇N₃O₆S.0.3TFA.0.75H₂O: C, 61.67; H, 7.01; N, 6.83. Found: C,61.78; H, 6.66; N, 6.63.

EXAMPLE A143-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (benzo[1,3]dioxol-5-ylmethyl)-amide

IR (neat or KBr cm⁻¹) 3302, 2922, 2351, 2333, 1768, 1750, 1646, 1537; ¹HNMR (DMSO-d₆) δ 9.36 (s, 1H), 8.44 (s, 1H), 8.13 (d, J=7.9 1H),7.34-7.13 (m, 5H), 6.99-6.77 (m, 4H), 6.78 (d, J=7.7, 1H), 5.93 (d,J=7.1, 2H), 5.15 (d, J=7.0, 1H), 5.08 (d, J=7.8, 1H), 4.43 (d, J=9.32,2H), 4.34 (m, 2H), 4.12 (d, J=6.18, 1H), 4.08 (d, J=6.08, 1H), 2.86-2.67(m, 2H), 2.55 (s, 1H), 1.81 (s, 3H), 1.51 (s, 3H), 1.39 (s, 3H); Anal.Calcd C₃₂H₃₅N₃O₇S.0.65TFA.1.0H₂O: C, 57.31; H, 5.44; N, 6.02. Found: C,57.58; H, 5.47; N, 5.85.

EXAMPLE A15(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (furan-2-ylmethyl)-amide

IR (neat or KBr cm⁻¹) 3311, 2931, 2360, 2333, 1732, 1718, 1695, 1646; ¹HNMR (DMSO-d₆) δ 9.36 (s, 1H), 8.44 (t, J=6.98, 1H), 8.13 (d, J=7.9 1H),7.53 (s, 1H), 7.34-7.13 (m, 5H), 6.95 (t, J=7.8, 1H), 6.78 (d, J=7.7,1H), 6.56 (d, J=7.4, 1H), 6.35 (d, J=7.1, 1H), 6.26 (d, J=7.12, 1H),5.15 (d, J=7.0, 1H), 5.08 (d, J=7.8, 1H), 4.45 (d, J=7.5, 1H), 4.34-4.22(m, 4H), 4.20 (m, 2H), 2.86-2.67 (m, 2H), 1.81 (s, 3H), 1.51 (s, 3H),1.39 (s, 3H); Anal. Calcd C₂₉H₃₃N₃O₆S.0.2TFA.1.0H₂O: C, 59.60; H, 5.99;N, 7.09. Found C, 59.68, H, 5.73; N, 6.97.

EXAMPLE A16(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (R)-chroman-4-ylamide

White solid: mp=135-136° C.; IR (cm⁻¹) 3312, 2928, 1644, 1584, 1520,1489, 1454, 1283, 1105; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.55 (d, J=8.2,1H), 8.20 (d, J=8.9, 1H), 7.36 (d, J=7.2, 2H,) 7.26-7.07 (m, 5H);6.95-6.90 (m, 1H), 6.81-6.73 (m, 3H), 6.54 (d, J=7.2, 1H), 5.47 (d,J=6.9, 1H), 5.16 (d, J=8.9, 1H), 5.01 (d, J=8.9, 1H), 4.54-4.32 (m, 4H),4.22-4.12 (m, 2H), 2.94-2.64 (m, 2H), 2.10-1.90 (m, 2H), 1.80 (s, 3H),1.49 (s, 3H), 1.41 (s, 3H); Anal. Calcd for C₃₃H₃₇N₃O₆S.1.25H₂O: C,63.29; H, 6.36; N, 6.71. Found: C, 63.22; H, 6.18; N, 6.51.

EXAMPLE A17(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-chroman-4-ylamide

White solid: mp=135-136° C.; IR (cm⁻¹) 3311, 2928, 1644, 1584, 1520,1489, 1454, 1283, 1105; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.49 (d, J=8.2,1H), 8.23 (d, J=8.4, 1H); 7.33-7.10 (m, 7H), 6.94-6.75 (m, 4H), 6.54 (d,J=7.7, 1H), 5.34 (d, J=7.2, 1H), 5.14 (d, J=8.9, 1H), 5.01 (d, J=8.9,1H), 4.54-4.30 (m, 4H), 4.24-4.10 (m, 2H), 2.82-2.62 (m, 2H), 2.10-1.90(m, 2H), 1.79 (s, 3H), 1.49 (s, 3H), 1.45 (s, 3H); Anal. Calcd forC₃₃H₃₇N₃O₆S.0.25H₂O: C, 65.17; H, 6.21; N, 6.91. Found: C, 65.24; H,6.28; N, 6.95.

EXAMPLE A18(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (R)-thiochroman-4-ylamide

White solid: mp=125-127° C.; IR (cm⁻¹) 3313, 2926, 1644, 1585, 1520,1455, 1285, 1081, 1048; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.61 (d, J=8.3,1H), 8.20 (d, J=8.6, 1H), 7.38-6.90 (m, 10H), 6.76 (d, J=8.1, 1H), 6.54(d, J=7.9, 1H), 5.46 (d, J=6.6, 1H), 5.17 (d, J=9.0, 1H), 5.01 (d,J=9.0, 1H), 4.56-4.21 (m, 4H), 3.20-2.61 (m, 4H), 2.30-2.00 (m, 2H),1.79 (s, 3H), 1.49 (s, 3H), 1.41 (s, 3H); Anal. Calcd forC₃₁H₃₇N₃O₅S₂.0.5 H₂O: C, 63.03; H, 6.09; N, 6.68. Found: C, 62.84; H,6.29; N, 6.38.

EXAMPLE A19(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-thiochroman-4-ylamide

White solid: mp=125-127° C.; IR.(cm⁻¹) 3312, 2927, 1644, 1585, 1520,1455, 1372, 1285; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.47 (d, J=7.5, 1H),8.23 (d, J=7.7, 1H), 7.37-6.91 (m, 10H), 6.76 (d, J=8.6, 1H), 6.54 (d,J=7.5, 1H), 5.33 (d, J=6.8, 1H), 5.15 (d, J=9.0, 1H), 5.00 (d, J=9.0,1H), 4.60-4.30 (m, 4H), 3.20-2.62 (m, 4H), 2.30-2.10 (m, 2H), 1.79 (s,3H), 1.49 (s, 3H), 1.46 (s, 3H); Anal. Calcd for C₃₃H₃₇N₃O₅S₂.1.75H₂O:C, 60.86; H, 6.27; N, 6.45. Found: C, 60.57; H, 5.90; N, 6.32.

EXAMPLE A20(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid cyclopropylmethyl-amide

¹H NMR (DMSO-d₆) δ 9.32 (s, 1H), 8.08 (d, J=8.4, 1H), 7.98 (t, J=6.0,1H), 7.33 (d, J=6.9, 2H), 7.24 (t, J=7.2, 2H), 7.16 (t, J=7.1, 1H), 6.94(t, J=7.8, 1H), 6.88 (d, J=7.1, 1H), 6.55 (d, J=6.6, 1H), 5.09 (d,J=9.1, 1H), 5.00 (d, J=9.1, 1H), 4.46 (d, J=3.4, 1H), 4.41 (s, 1H), 4.40(m, 1H), 2.95 (m, 2H), 2.87-2.65 (m, 2H), 1.82 (s, 3H), 1.50 (s, 3H),1.38 (s, 3H), 0.89 (m, 1H), 0.38 (m, 2H), 0.16 (m, 2H); HRMS (ESI) m/zcalcd for C₂₇H₃₅N₃O₅SNa (M+Na)⁺ 548.2190, found 548.2180.

EXAMPLE A21(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid cyclohexylamide

¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.18 (d, J=8.4, 1H), 7.79 (d, J=8.0,1H), 7.35-7.12 (m, 5H), 6.92 (t, J=7.9, 1H), 6.75 (d, J=8.1, 1H), 6.53(d, J=7.5, 1H), 5.29 (d, J=7.0, 1H), 5.09 (d, J=9.2, 1H), 5.00 (d,J=9.2, 1H), 4.56-4.37 (m, 2H), 3.61-3.49 (m, 2H), 2.89-2.65 (m, 2H),1.80 (s, 3H), 1.79-1.58 (m, 5H), 1.48 (s, 3H), 1.36 (s, 3H), 1.35-1.02(m, 5H); Anal. Calcd for C₃₀H₃₉N₃O₅S: C, 65.07; H, 7.10; N, 7.59. Found:C, 65.39; H, 6.92; N, 7.32.

EXAMPLE A223-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid-(4-methyl-pyridin-3-ylmethyl)amide

¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.43 (s, 1H), 8.39 (t, J=6.0, 1H), 8.29(d, J=4.9, 1H), 8.11 (d, J=8.2, 1H), 7.31 (d, J=7.0, 2H), 7.24 (d,J=7.0, 2H), 7.17 (m, 2H), 6.95 (t, J=7.7, 1H), 6.78 (d, J=7.3, 1H), 6.55(d, J=7.0, 1H), 5.42 (d, J=6.7, 1H), 5.14 (d, J=9.1, 1H), 5.01 (d,J=9.2, 1H), 4.54-4.40 (m, 4H), 4.17 (dd, J=5.1, 15.1, 1H), 2.82 (dd,J=3.0, 14.1, 1H), 2.72 (dd, J=10.1, 14.2, 1H), 2.30 (s, 3H), 1.82 (s,3H), 1.49 (s, 3H), 1.32 (s, 3H); Anal. Calcd for C₃₁H₃₆N₄O₅S.2H₂O: C,60.76, H, 6.58; N, 9.14; S, 5.23. Found: C, 60.89; N, 6.26; H, 8.90; S,5.05.

EXAMPLE A23(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (thiophen-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.51 (t, J=6.0, 1H), 8.08 (d, J=8.4,1H), 7.40-7.12 (m, 6H), 7.04-6.88 (m, 3H), 6.80 (d, J=7.4, 1H), 6.57 (d,J=7.4, 1H), 5.12 (d, J=9.0, 1H), 5.02 (d, J=9.0, 1H), 4.58-4.30 (m, 5H),2.97-2.67 (m, 2H), 1.84 (s, 3H), 1.50 (s, 3H), 1.35 (s, 3H); HRMS (ESI)m/z calcd for C₂₉H₃₃N₃O₅S₂Na (M+Na)⁺ 590.1754, found 590.1762; Anal.Calcd for C₂₉H₃₃N₃O₅S₂.0.5H₂O, 0.2TFA: C, 58.90, H, 5.75; N, 7.01.Found: C, 58.85; N, 5.71; H, 6.95.

EXAMPLE A24(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (5-chloro-benzo[b]thiophen-3-ylmethyl)-amide

IR (neat, cm⁻¹) 3401, 1643, 1531, 1443, 1284, ¹H NMR (DMSO-d₆) δ 9.37(s, 1H), 8.54 (t, J=5.7, 1H), 8.16 (d, J=8.4, 1H), 8.00-7.95 (m, 2H),7.67 (s, 1H), 7.38 (dd, J=8.6, 2.0, 1H), 7.32-7.11 (m, 5H), 6.97 (t,J=7.7, 1H), 6.77 (d, J=7.9, 1H), 6.55 (d, J=7.1, 1H), 5.46 (s br, 1H),5.14 (d, J=9.3, 1H), 5.02 (d, J=9.5, 1H), 4.62-4.40 (m, 5H), 2.87-2.67(m, 2H), 1.82 (s, 3H), 1.47 (s, 3H), 1.30 (s, 3H); HRMS (ESI) m/z calcdfor C₃₃H₃₄N₃O₅S₂ClNa (M+Na)⁺ 674.1521, found 674.1547; Anal. Calcd forC₃₃H₃₄ClN₃O₅S₂.H₂O: C, 59.13; H, 5.41; N, 6.27. Found: C, 59.19; H,5.41; N, 6.08.

EXAMPLE A25(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid cyclopropylamide

¹H NMR (DMSO-d₆) δ 9.32 (s, 1H), 8.20 (d, J=8.4, 1H), 7.80 (d, J=8.0,1H), 7.36-7.10 (m, 5H), 6.90 (t, J=7.9, 1H), 6.75 (d, J=8.1, 1H), 6.55(d, J=7.5, 1H), 5.35 (d, J=7.0, 1H), 5.15 (d, J=9.2, 1H), 5.02 (d,J=9.2, 1H), 4.59-4.30 (m, 3H), 2.89-2.65 (m, 3H), 1.82 (s, 3H), 1.48 (s,3H), 1.36 (s, 3H), 0.73-0.59 (m, 2H), 0.57-0.33 (m, 2H); Anal. Calcd forC₂₇H₃₃N₃O₅S: C, 63.38; H, 6.50; N, 8.21. Found: C, 63.39; H, 6.82; N,8.32.

EXAMPLE A26(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid cyclobutylamide

¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.18 (d, J=8.4, 1H), 7.79 (d, J=8.0,1H), 7.40-7.12 (m, 5H), 6.90 (t, J=7.9, 1H), 6.75 (d, J=8.1, 1H), 6.47(d, J=7.5, 1H), 5.34 (d, J=7.0, 1H), 5.14 (d, J=9.2, 1H), 4.99 (d,J=9.2, 1H), 4.55-4.32 (m, 3H), 2.90-2.65 (m, 3H), 1.81 (s, 3H), 1.49 (s,3H), 1.36 (s, 3H), 1.34-1.02 (m, 6H); Anal. Calcd for C₂₈H₃₅N₃O₅S: C,63.97; H, 6.71; N, 7.99. Found: C, 64.05; H, 6.55; N, 8.07.

EXAMPLE A27(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid cyclopentylamide

¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.15 (d, J=8.4, 1H), 7.80 (d, J=8.0,1H), 7.38-7.11 (m, 5H), 6.88 (t, J=7.9, 1H), 6.75 (d, J=8.1, 1H), 6.52(d, J=7.4, 1H), 5.30 (d, J=7.0, 1H), 5.12 (d, J=9.2, 1H), 4.99 (d,J=9.2, 1H), 4.63-4.42 (m, 3H), 2.96-2.67 (m, 3H), 1.81 (s, 3H),1.78-1.57 (m, 4H), 1.50 (s, 3H), 1.36 (s, 3H), 1.34-1.02 (m, 4H); Anal.Calcd for C₂₉H₃₇N₃O₅S: C, 64.54; H, 6.91; N, 7.79. Found: C, 64.22; H,6.78; N, 7.93.

EXAMPLE A28(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (2-phenyl-cyclopropyl)-amide

IR (neat, cm⁻¹) 3425, 1637, 1525, 1455, 1278, ¹H NMR (DMSO-d₆) δ 9.37(s, 1H), 8.26 (m, 1H), 8.17 (d, J=7.7, 1H), 7.36-7.05 (m, 10H), 6.93 (t,J=7.7, 1H), 6.77 (d, J=8.1, 1H), 6.54 (d, J=7.0, 1H), 5.38 (d, J=6.2,1H), 5.12 (d, J=9.0, 1H), 5.01 (d, J=9.3, 1H), 4.49-4.36 (m, 3H),2.84-2.68 (m, 2H), 1.92-1.82 (m, 2H), 1.81 (s, 3H), 1.50 (s, 3H), 1.37(s, 3H), 1.22-1.09 (m, 2H); HRMS (ESI) m/z calcd for C₃₃H₃₇N₃O₅SNa(M+Na)⁺ 610.2346, found 610.2335; Anal. Calcd for C₃₃H₃₇N₃O₅S.0.8H₂O: C,65.82; H, 6.46; N, 6.98. Found: C, 65.77; H, 6.34; N, 6.84.

EXAMPLE A29(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (R)-indan-1-ylamide

White solid: mp 128-130° C.; IR (neat, cm⁻¹) 3306, 1632, 1537, 1454,1286; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.37 (d, J=8.1, 1H), 8.17 (d,J=8.4, 1H), 7.38-7.06 (m, 9H), 6.93 (t, J=7.5, 1H), 6.77 (d, J=7.5, 1H),6.54 (d, J=7.5, 1H), 5.44 (d, J=6.9, 1H), 5.35 (dd, J=16.7, 8.1, 1H),5.15 (d, J=8.8, 1H), 5.01 (d, J=8.8, 1H), 4.58-4.32 (m, 3H), 2.95-2.70(m, 2H), 2.40-2.20 (m, 2H), 1.90-1.70 (m, 2H), 1.81 (s, 3H), 1.51 (s,3H), 1.43 (s, 3H); Anal. Calcd for C₃₃H₃₇N₃O₅S.0.75H₂O: C, 65.92; H,6.45; N, 6.99. Found: C, 65.57; H, 6.31; N, 6.82.

EXAMPLE A30N-{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(1-morpholin-4-yl-methanoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-3-hydroxy-2-methyl-benzamide

IR (neat, cm⁻¹) 3341, 2955, 1640, 1524, 1455, 1284, 1113, ¹H NMR(DMSO-d₆) δ 9.36 (s, 1H), 8.24 (d, J=8.6, 1H), 7.36-7.13 (m, 5H), 6.94(t, J=7.7, 1H), 6.78 (d, J=7.5, 1H), 6.53 (d, J=7.5, 1H), 5.34 (m, 1H),5.12 (d, J=9.2, 1H), 5.04 (d, J=9.2, 1H), 4.50 (m, 1H), 4.33-4.30 (m,2H), 3.78-3.51 (m, 8H), 2.81-2.62 (m, 2H), 1.80 (s, 3H), 1.56 (s, 3H),1.38 (s, 3H); HRMS (ESI) m/z calcd for NaC₂₈H₃₅N₃O₆S (M+Na)⁺ 564.2139,found 564.2116.

EXAMPLE A31(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid cycloheptylamide

¹H NMR (DMSO-d₆) δ 9.32 (s, 1H), 8.20 (d, J=8.4, 1H), 7.78 (d, J=8.0,1H), 7.40-7.12 (m, 5H), 6.92 (t, J=7.9, 1H), 6.73 (d, J=8.1, 1H), 6.50(d, J=7.5, 1H), 5.29 (d, J=7.0, 1H), 5.19 (d, J=9.2, 1H), 5.03 (d,J=9.2, 1H), 4.62-4.37 (m, 3H), 2.92-2.67 (m, 3H), 1.80 (s, 3H),1.79-1.01 (m, 18H); Anal. Calcd for C₃₁H₄₁N₃O₅S: C, 65.58; H, 7.28; N,7.40. Found: C, 65.74; H, 7.07; N, 7.53.

EXAMPLE A32(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-cyclohex-2-enylamide

White solid: mp 177-179° C.; IR (neat, cm⁻¹) 3319, 2943, 1637, 1531,1455, 1361, 1284; ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.16 (d, J=7.6, 1H),7.95 (d, J=7.7, 1H), 7.38-7.10 (m, 5H), 6.93 (t, J=7.6, 1H), 6.76 (d,J=7.6, 1H), 6.53 (d, J=7.6, 1H), 5.80-5.70 (m, 1H), 5.50-5.40 (m, 1H),5.35 (d, J=6.9, 1H), 5.11 (d, J=9.2, 1H), 4.99 (d, J=9.2, 1H), 4.55-4.30(m, 4H), 2.84-2.62 (m, 2H), 2.00-1.62 (m, 9H), 1.48 (s, 3H), 1.37 (s,3H); Anal. Calcd for C₃₀H₃₇N₃O₅S.0. 5H₂O: C, 64.26; H, 6.83; N, 7.49.Found: C, 64.21; H, 6.74; N, 7.36.

EXAMPLE A33N-{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(1-thiomorpholin-4-yl-methanoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-3-hydroxy-2-methyl-benzamide

¹H NMR (DMSO-d₆) δ 9.40 (s, 1H), 8.30 (d, J=8.4, 1H), 7.40-7.16 (m, 5H),6.97 (t, J=7.5, 1H), 6.80 (d, J=8.1, 1H), 6.57 (d, J=7.1, 1H), 5.40 (d,J=7.1, 1H), 5.18 (d, J=9.2, 1H), 5.06 (d, J=9.7, 1H), 4.54 (m, 1H),4.35-4.19 (m, 2H), 3.68-3.59 (m, 2H), 3.28-3.10 (m, 2H), 2.87-2.44 (m,6H), 1.83 (s, 3H), 1.60 (s, 3H), 1.37 (s, 3H); HRMS (ESI) m/z calcd forC₂₈H₃₅N₃O₅S₂Na (M+Na)⁺ 580.1910, found 580.1922.

EXAMPLE A34N-{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(1-piperidin-1-yl-methanoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-3-hydroxy-2-methyl-benzamide

IR (neat, cm⁻¹) 3389, 2931, 1631, 1461, 1284, ¹H NMR (DMSO-d₆) δ 9.36(s, 1H), 8.05 (d, J=8.1, 1H), 7.38-7.12 (m, 5H), 6.94 (t, J=7.7, 1H),6.77 (d, J=7.3, 1H), 6.53 (d, J=7.3, 1H), 5.29 (d, J=7.1, 1H), 5.14-5.01(m, 2H), 4.50 (m, 1H), 4.32-4.19 (m, 2H), 3.78-3.67 (m, 2H), 3.42-3.09(m, 2H), 2.81-2.62 (m, 2H), 1.80 (s, 3H), 1.75-1.35 (m, 6H), 1.57 (s,3H), 1.36 (s, 3H); HRMS (ESI) m/z calcd for C₂₉H₃₇N₃O₅SNa (M+Na)⁺562.2346, found 562.2327; Anal. Calcd for C₂₉H₃₇N₃O₅S.0.8H₂O: C, 62.86;H, 7.02; N, 7.58. Found: C, 62.83; H, 6.95; N, 7.38.

EXAMPLE A35(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-indan-1-ylamide

White solid: mp 204-206° C.; IR (neat, cm⁻¹) 3307, 1633, 1537, 1454,1287; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.37 (d, J=8.1, 1H), 8.17 (d,J=8.4, 1H), 7.38-7.06 (m, 9H), 6.93 (t, J=7.5, 1H), 6.77 (d, J=7.5, 1H),6.54 (d, J=7.5, 1H), 5.44 (d, J=6.9,1H), 5.35 (dd, J=16.7, 8.1, 1H),5.13 (d, J=8.8, 1H), 5.04 (d, J=8.8, 1H), 4.58-4.32 (m, 3H), 2.95-2.70(m, 2H), 2.40-2.20 (m, 2H), 1.90-1.70 (m, 2H), 1.81 (s, 3H), 1.51 (s,3H), 1.43 (s, 3H); Anal. Calcd for C₃₃H₃₇N₃O₅S: C, 67.44; H, 6.35; N,7.15. Found: C, 67.10; H, 6.43; N, 7.02.

EXAMPLE A36(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (4-methyl-cyclohexyl)-amide

White solid: mp 192-194° C.; IR (neat, cm⁻¹) 3298, 2955, 1638, 1531,1449, 1349, 1284, 1099; ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.22-8.21 (m,1H), 7.82-7.70 (m, 1H), 7.34-7.14 (m, 5H), 6.95-6.90 (m, 1H), 6.76 (d,J=8.1, 1H), 6.53 (d, J=7.3, 1H), 5.33 (d, J=5.9, 1H), 5.13-4.94 (m, 2H),4.60-4.30 (m, 3H), 3.80-3.40 (m, 1H), 2.81-2.68 (m, 2H), 1.79 (s, 3H),1.80-1.13 (m, 15H), 0.89-0.82 (m, 3H); Anal. Calcd for C₃₁H₄₁N₃O₅S.1H₂O:C, 63.57; H, 7.40; N, 7.17. Found: C, 63.73; H, 7.36; N, 6.91.

EXAMPLE A37(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (tetrahydro-furan-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.14 (d, J=8.8, 1H), 8.03 (t, J=5.0,1H), 7.32-7.15 (m, 5H), 6.94 (t, J=7.5, 1H), 6.79 (d, J=7.5, 1H), 6.57(d, J=7.5, 1H), 5.49 (d, J=5.5, 1H), 5.12 (d, J=9.3, 1H), 5.02 (d,J=9.3, 1H), 4.52-4.12 (m, 3H), 3.79-3.53 (m, 5H), 3.31-3.20 (m, 2H);2.92-2.62 (m, 2H), 1.90-1.71 (m, 2H), 1.69 (s, 3H), 1.48 (s, 3H), 1.34(s, 3H); Anal. Calcd for C₂₉H₃₇N₃O₆S.0.5H₂O: C, 61.68; H, 6.78; N, 7.44.Found: C, 61.52; H, 6.62; N, 7.53.

EXAMPLE A38(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (R)-cyclohex-2-enylamide

White solid: mp=193-195° C.; IR (neat, cm⁻¹) 3316, 2931, 1637, 1584,1519, 1449, 1349, 1279, 1085; ¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.14 (d,J=8.4, 1H), 8.03 (d, J=8.1, 1H), 7.35-7.12 (m, 5H), 6.93 (t, J=7.2, 1H),6.77 (d, J=7.2, 1H), 6.53 (d, J=7.2, 1H), 5.79 (d, J=9.9, 1H), 5.52 (d,J=9.9, 1H), 5.36 (d, J=6.8, 1H), 5.10 (d, J=9.2, 1H), 4.99 (d, J=9.2,1H), 4.48-4.20 (m, 4H), 2.84-2.62 (m, 2H), 2.00-1.85 (m, 2H), 1.80 (s,3H), 1.80-1.40 (m, 4H), 1.48 (s, 3H), 1.37 (s, 3H); Anal. Calcd forC₃₀H₃₇N₃O₅S.0.25H₂O: C, 64.60; H, 6.78; N, 7.53. Found: C, 64.83; H,6.72; N, 7.44.

EXAMPLE A39(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (cyclopent-1-enylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.11 (d, J=7.9, 1H), 8.06 (t, J=5.7,1H), 7.33-7.13 (m, 5H), 6.94 (t, J=7.7, 1H), 6.77 (d, J=8.1, 1H), 6.53(d, J=7.5, 1H), 5.50 (s, 1H), 5.45 (d, J=6.6, 1H), 5.11 (d, J=9.0, 1H),4.98 (d, J=9.2, 1H), 4.47-4.38 (m, 3H), 3.81 (dd, J=15.8, 6.4, 1H), 3.61(dd, J=15.9, 5.3, 1H), 2.84-2.67 (m, 2H), 2.20-2.15 (m, 4H), 1.83-1.73(m, 2H), 1.80 (s, 3H), 1.49 (s, 3H), 1.35 (s, 3H); HRMS (ESI) m/z calcdfor C₃₀H₃₇N₃O₅SNa (M+Na)⁺ 574.2346, found 574.2354.

EXAMPLE A40(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (thiophen-3-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.40 (s, 1H), 8.44 (t, J=5.7, 1H), 8.16 (d, J=8.1,1H), 7.45 (m, 1H), 7.35-7.15 (m, 6H), 7.05 (d, J=6.0, 1H), 6.97 (t,J=7.7, 1H), 6.80 (d, J=8.1, 1H), 6.57 (d, J=7.3, 1H), 5.52 (d, J=6.4,1H), 5.15 (d, J=9.3, 1H), 5.03 (d, J=9.2, 1H), 5.12-4.37 (m, 4H),2.86-2.67 (m, 2H), 4.18 (dd, J=15.2, 5.1, 1H), 2.89-2.70 (m, 2H), 1.84(s, 3H), 1.52 (s, 3H), 1.36 (s, 3H); HRMS (ESI) m/z calcd forC₂₉H₃₃N₃O₅S₂Na (M+Na)⁺ 590.1754, found 590.1734; Anal. Calcd forC₂₉H₃₃N₃O₅S₂.0.6H₂O: C, 60.20; H, 5.96; N, 7.26. Found: C, 60.26; H,6.02; N, 7.08.

EXAMPLE A41(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (thiazol-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.82 (t, J=5.9, 1H), 8.11 (d, J=8.2,1H), 7.68 (d, J=3.3, 1H), 7.57 (d, J=3.1, 1H), 7.33-7.13 (m, 5H), 6.94(t, J=7.7, 1H), 6.77 (d, J=7.3, 1H), 6.54 (d, J=6.6, 1H), 5.49 (d,J=6.4, 1H), 5.11 (d, J=9.3, 1H), 5.02 (d, J=9.3, 1H), 4.64-4.38 (m, 5H),2.88-2.68 (m, 2H), 1.82 (s, 3H), 1.51 (s, 3H), 1.36 (s, 3H); HRMS (ESI)m/z calcd for C₂₈H₃₂N₄O₅S₂Na (M+Na)⁺ 591.1706, found 591.1710.

EXAMPLE A423-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (5,6,7,8-tetrahydro-quinolin-5-yl)-amide

Purified by Prep HPLC using 15% CH₃CN/H₂O (0.1% TFA) to 95% CH₃CN at 254nm. White foam; IR (cm⁻¹) 3298, 2943, 1637, 1584, 1531, 1447, 1366; ¹HNMR (DMSO-d₆) δ 9.36 (s, 1H), 8.34-8.28 (m, 2H), 8.20 (d, J=8.6, 1H),7.55 (d, J=6.9, 1H), 7.27-6.90 (m, 7H), 6.76 (d, J=8.1, 1H), 6.53 (d,J=7.5, 1H), 5.37 (d, J=6.7, 1H), 5.10-5.00 (m, 1H), 5.14 (d, J=9.3, 1H),5.01 (d, J=9.3, 1H), 4.58-4.40 (m, 2H), 4.40 (s, 1H), 2.90-2.60 (m, 2H),2.00-1.80 (m, 6H), 1.79 (s, 3H), 1.49 (s, 3H), 1.42 (s, 3H); Anal. Calcdfor C₃₃H₃₈N₄O₅S.0.5TFA.0.6H₂O: C, 60.90; H, 5.97; N, 8.36. Found: C,60.87; H, 6.28; N, 8.44.

EXAMPLE A433-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (5,6,7,8-tetrahydro-quinolin-5-yl)-amide

Purified by Prep HPLC using 15% CH₃CN/H₂O (0.1% TFA) to 95% CH₃CN at 254nm.

White foam; IR (cm⁻¹) 3298, 2942, 1637, 1584, 1531, 1447, 1366, 1208,1091; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.47 (d, J=8.8, 1H), 8.30 (dd,J=4.8, 1.2, 1H), 8.18 (d, J=8.4, 1H), 7.63 (d, J=7.2, 1H), 7.37-6.90 (m,7H), 6.76 (d, J=8.1, 1H), 6.55 (d, J=7.5, 1H), 5.45 (d, J=6.9, 1H),5.50-5.05 (m, 1H), 5.16 (d, J=8.9, 1H), 5.01 (d, J=8.9, 1H), 4.52-4.49(m, 2H), 4.42 (s, 1H), 3.00-2.65 (m, 2H), 2.00-1.60 (m, 6H), 1.80 (s,3H), 1.50 (s, 3H), 1.42 (s, 3H); Anal. Calcd forC₃₃H₃₈N₄O₅S.0.5TFA.0.6H₂O: C, 60.90; H, 5.97; N, 8.36. Found: C, 60.87;H, 6.28; N, 8.44.

EXAMPLE A443-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (1H-indazol-3-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 12.81 (s, 1H), 9.34 (s, 1H), 8.51 (t, J=5.5, 1H),8.14 (d, J=8.2, 1H), 7.86-6.56 (m, 12H), 5.35 (d, J=6.6, 1H), 5.12 (d,J=9.1, 1H), 5.03 (d, J=9.1, 1H), 4.74-4.41 (m, 5H), 4.49 (s, 1H),2.91-2.69 (m, 2H), 1.84 (s, 3H), 1.47 (s, 3H), 1.30 (s, 3H); Anal. Calcdfor C₃₂H₃₅N₅O₅S.0.5 EtOAc: C, 63.23; H, 6.09; N, 10.85; S, 4.97. Found:C, 63.12; H, 6.27; N, 10.78; S, 4.86.

EXAMPLE A45(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (furan-3-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.40 (s, 1H), 8.34 (t, J=5.7, 1H), 8.18 (d, J=8.4,1H), 7.57 (m, 2H), 7.36-7.15 (m, 5H), 6.97 (t, J=7.7, 1H), 6.80 (d,J=7.9, 1H), 6.57 (d, J=7.3, 1H), 6.41 (s, 1H), 5.47 (d, J=6.2, 1H), 5.12(d, J=9.2, 1H), 5.00 (d, J=9.2, 1H), 4.46-4.39 (m, 3H), 4.22-3.98 (m,2H), 2.85-2.67 (m, 2H), 1.81 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3H); HRMS(ESI) m/z calcd for C₂₉H₃₄N₃O₆S (M+H)⁺ 552.2168, found 551.2173; Anal.Calcd for C₂₉H₃₃N₃O₆S: C, 61.63; H, 6.15; N, 7.43. Found: C, 61.76; H,6.10; N, 7.24.

EXAMPLE A46(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (tetrahydro-furan-3-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.14-8.03 (m, 2H), 7.34-7.13 (m, 5H),6.93 (t, J=7.9, 1H), 6.76 (d, J=8.1, 1H), 6.52 (d, J=7.5, 1H), 5.43 (m,1H), 5.10 (d, J=9.3, 1H), 4.99 (d, J=9.2, 1H), 4.46-4.35 (m, 3H),3.69-3.50 (m, 4H), 3.40-3.22 (m, 1H), 3.12-2.95 (m, 2H), 2.84-2.66 (m,2H), 2.36-2.27 (m, 1H), 1.87-1.76 (m, 1H), 1.80 (s, 3H), 1.49 (s, 3H),1.34 (s, 3H); HRMS (ESI) m/z calcd for C₂₉H₃₇N₃O₆SNa (M+Na)⁺ 556.2470,found 556.2481; Anal. Calcd for C₂₉H₃₇N₃O₆S.0.75H₂Q: C, 61.19; H, 6.72;N, 7.38. Found: C, 61.24; H, 6.59; N, 7.01.

EXAMPLE A473-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (4,5,6,7-tetrahydro-benzofuran -4-yl)-amide

White foam; IR (cm⁻¹) 3331, 2943, 1643, 1590, 1522, 1445, 1364, 1282; ¹HNMR (DMSO-d₆) δ 9.35 (s, 1H), 8.21-8.16 (m, 2H), 7.42-7.14 (m, 6H),6.96-6.90 (m, 1H), 6.76 (d, J=8.2, 1H), 6.54 (d, J=7.2, 1H), 6.28 (d,J=1.8, 1H), 5.39 (d, J=6.9, 1H), 5.13 (d, J=9.0, 1H), 5.02 (d, J=9.0,1H), 4.90-4.70 (m, 1H), 4.55-4.30 (m, 3H), 2.89-2.68 (m, 2H), 1.81 (s,3H), 2.00-1.50 (m, 6H), 1.48 (s, 3H), 1.39 (s, 3H); Anal. Calcd forC₃₂H₃₇N₃O₆S.0.5H₂O: C, 63.98; H, 6.38; N, 6.99. Found: C, 63.93; H,6.44; N, 6.68.

EXAMPLE A483-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (4,5,6,7-tetrahydro-benzofuran -4-yl)-amide

White foam; IR (cm⁻¹) 3316, 2935, 1754, 1657, 1642, 1584, 1530, 1454,1357, 1284, 1209; ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.19 (d, J=8.8, 1H),8.14 (d, J=8.1, 1H), 7.43-7.14 (m, 6H), 6.96-6.91 (m, 1H), 6.77 (d,J=7.9, 1H), 6.54 (d, J=7.5, 1H), 6.38 (d, J=1.9, 1H), 5.32 (d, J=6.9,1H), 5.13 (d, J=9.0, 1H), 5.00 (d, J=9.0, 1H), 4.83-4.50 (m, 1H),4.52-4.12 (m, 3H), 2.82-2.62 (m, 2H), 1.79 (s, 3H), 2.00-1.50 (m, 6H),1.47 (s, 3H), 1.41 (s, 3H); Anal. Calcd for C₃₂H₃₇N₃O₆S.0.5H₂O: C,63.98; H, 6.38; N, 6.99. Found: C, 64.03; H, 6.37; N, 6.66.

EXAMPLE A493-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (4,5,6,7-tetrahydro-benzo[b]thiophen-4-yl)-amide

White foam; IR (cm⁻¹) 3317, 2943, 1643, 1525, 1455, 1367, 1256; ¹H NMR(DMSO-d₆) δ 9.36 (s, 1H), 8.36 (d, J=8.6, 1H), 8.18 (d, J=8.2, 1H), 7.37(d, J=7.2, 1H), 7.28-6.75 (m, 8H), 6.54 (d, J=7.2, 1H), 5.41 (d, J=6.9,1H), 5.14 (d, J=8.8, 1H), 4.99 (d, J=8.8, 1H), 5.00-4.56 (m, 1H),4.52-4.30 (m, 3H), 2.80-2.60 (m, 2H), 1.81 (s, 3H), 2.00-1.60 (m, 6H),1.49 (s, 3H), 1.41 (s, 3H); Anal. Calcd for C₃₂H₃₇N₃O₅S₂.0.5H₂O: C,62.31; H, 6.21; N, 6.81. Found: C, 62.30; H, 6.17; N, 6.60.

EXAMPLE A503-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (4,5,6,7-tetrahydro-benzo[b]thiophen-4-yl)-amide

White foam; IR (cm⁻¹) 3321, 2935, 1642, 1585, 1530, 1372, 1283, 1045; ¹HNMR (DMSO-d₆) δ 9.35 (s, 1H), 8.24 (d, J=8.8, 1H), 8.20 (d, J=8.4, 1H),7.31 (d, J=7.2, 1H), 7.23-6.70 (m, 8H), 6.54 (d, J=7.2, 1H), 5.32 (d,J=6.4, 1H), 5.13 (d, J=9.2, 1H), 5.01 (d, J=9.2, 1H), 5.00-4.60 (m, 1H),4.60-4.30 (m, 3H), 2.80-2.60 (m, 2H), 1.80 (s, 3H), 2.00-1.60 (m, 6H),1.47 (s, 3H), 1.42 (s, 3H); Anal. Calcd for C₃₂H₃₇N₃O₅S₂: C, 63.24; H,6.14; N, 6.91. Found: C, 63.59; H, 6.20; N, 6.68.

EXAMPLE A513-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide

Purified by Prep HPLC using 15% CH₃CN/H₂O (0.1% TFA) to 95% CH₃CN at 254nm. White foam; IR (cm⁻¹) 3296, 2966, 1644, 1538, 1554, 1373, 1284,1046; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.41 (d, J=7.3, 1H), 8.33 (d,J=4.4, 1H), 8.19 (d, J=9.2, 1H), 7.55 (d, J=7.2, 1H), 7.36 (d, J=7.2,1H), 7.28-6.90 (m, 6H), 6.76 (d, J=7.9, 1H), 6.53 (d, J=6.6, 1H), 5.39(d, J=7.2, 1H), 5.32 (dd, J=14.9, 7.3, 1H), 5.15 (d, J=9.0, 1H), 5.02(d, J=9.0, 1H), 4.54-4.34 (m, 3H), 3.00-2.60 (m, 4H), 2.44-2.30 (m, 1H),1.98-1.81 (m, 1H), 1.79 (s, 3H), 1.48 (s, 3H), 1.40 (s, 3H); Anal. Calcdfor C₃₂H₃₆N₄O₅S.0.25TFA.0.5H₂O: C, 62.33; H, 6.00; N, 8.95. Found: C,62.58; H, 6.15; N, 8.95.

EXAMPLE A523-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (6,7-dihydro-5H-[1]pyrindin-5-yl)-amide

Purified by Prep HPLC using 15% CH₃CN/H₂O (0.1% TFA) to 95% CH₃CN at 254nm. White foam; IR (cm⁻¹) 3296, 2966, 1643, 1539, 1554, 1373, 1284,1045; ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.59 (d, J=8.0, 1H), 8.32 (d,J=4.0, 1H), 8.16 (d, J=8.4, 1H), 7.57 (d, J=7.7, 1H), 7.36 (d, J=7.7,1H), 7.25-6.90 (m, 6H), 6.76 (d, J=8.0, 1H), 6.54 (d, J=7.7, 1H), 5.43(d, J=6.9, 1H), 5.36 (dd, J=16.0, 8.0, 1H), 5.14 (d, J=9.0, 1H), 5.01(d, J=9.0, 1H), 4.54-4.36 (m, 3H), 2.90-2.70 (m, 4H), 2.44-2.30 (m, 1H),1.84-1.70 (m, 1H), 1.80 (s, 3H), 1.51 (s, 3H), 1.42 (s, 3H); Anal. Calcdfor C₃₂H₃₆N₄O₅S.0.25TFA.0.5H₂O: C, 62.33; H, 6.00; N, 8.95. Found: C,62.41; H, 6.38; N, 8.81.

EXAMPLE A53(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (2-methyl-furan-3-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.20 (m, 1H), 8.14 (d, J=7.9, 1H),7.35-7.13 (m, 6H), 6.94 (t, J=7.7, 1H), 6.75 (d, J=8.0, 1H), 6.53 (d,J=7.5, 1H), 6.28 (s, 1H), 5.42 (d, J=6.6, 1H), 5.11 (d, J=9.0, 1H), 4.99(d, J=9.1, 1H), 4.46-4.38 (m, 3H), 4.12-3.92 (m, 2H), 2.84-2.66 (m, 2H),2.20 (s, 3H), 1.80 (s, 3H), 1.46 (s, 3H), 1.30 (s, 3H); HRMS (ESI) m/zcalcd for C₃₀H₃₆N₃O₆S (M+H)⁺ 566.2332, found 566.2325; Anal. Calcd forC₃₀H₃₅N₃O₆S.0.5H₂O: C, 62.70; H, 6.31; N, 7.31. Found: C, 62.82; H,6.19; N, 7.09.

EXAMPLE A54(R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (3-methyl-benzofuran-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.55 (t, J=5.5, 1H), 8.15 (d, J=8.3,1H), 7.52 (d, J=6.9, 1H, 7.51-7.36 (m, 3H), 7.28-7.18 (m, 5H), 6.96 (t,J=7.8, 1H), 6.78 (d, J=8.0, 1H), 6.55 (d, J=7.4, 1H), 5.42 (br s, 1H),5.12 (d, J=9.1, 1H), 5.00 (d, J=9.1, 1H), 4.48-4.39 (m, 5H), 2.83 (m,1H), 2.72 (dd, J=13.5, 10.7, 1H), 2.20 (s, 3H), 1.99 (s, 3H), 1.46 (s,3H), 1.27 (s, 3H); HRMS (ESI) m/z calcd for C₃₄H₃₈N₃O₆S (M+H)⁺ 616.2481,found 616.2464; Anal. Calcd for C₃₄H₃₇N₃O₆S: C, 66.32; H, 6.06; N, 6.82.Found: C, 60.06; H, 6.04; N, 6.71.

EXAMPLE A55(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid ((S)-6,8-difluoro-chroman-4-yl)-amide

White solid: ¹H NMR (DMSO₆) δ 9.36 (s, 1H), 8.49 (d, J=8.1, 1H), 8.21(d, J=8.6, 1H), 7.30-6.50 (m, 10H), 5.34 (d, J=6.2, 1H), 5.16 (d, J=9.3,1H), 5.10-490 (m, 2H), 4.55-4.20 (m, 3H), 2.80-2.60 (m, 2H), 2.10-1.95(m, 2H), 1.78 (s, 3H), 1.50 (s, 3H), 1.43 (s, 3H), 1.40-1.35 (m, 1H),1.30-1.20 (m, 1H); HRMS (ESI) m/z calcd for C₃₃H₃₆N₃O₆F₂S (M+H)⁺640.2293, found 640.2284.

EXAMPLE A56(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid ((S)-5-fluoro-indan-1-yl)-amide

White solid: ¹H NMR (DMSO) δ 9.36 (s, 1H), 8.33 (d, J=7.8, 1H), 8.20 (d,J=8.6, 1H), 7.30-6.50 (m, 1H), 5.37 (d, J=6.9, 1H), 5.30-5.20 (m, 1H),5.14 (d, J=8.9, 1H), 5.02 (d, J=8.9, 1H), 4.60-4.30 (m, 3H), 3.00-2.60(m, 4H), 2.50-2.30 (m, 1H), 2.00-1.80 (m, 1H), 1.19 (s, 3H), 1.48 (s,3H), 1.41 (s, 3H); HRMS (ESI) m/z calcd for C₃₃H₃₇N₃O₅FS (M+H)⁺606.2438, found 606.2441.

EXAMPLE A57N-{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(N′-methyl-N′-phenyl-hydrazinocarbonyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-3-hydroxy-2-methyl-benzamide

¹H NMR (DMSO-d₆) δ 10.12 (s, 1H), 9.37 (s, 1H), 8.18 (d, 1H, J=8.2),7.26-7.11 (m, 7H), 6.96-6.87 (m, 3H), 6.77 (d, 1H, J=7.3), 6.68 (t, 1H,J=7.1), 6.54 (d, 1H, J=7.5), 5.55 (d, 1H, J=6.6), 5.16 (d, 1H, J=9.3),5.04 (d, 1H, J=9.2), 4.48 (d, 1H, J=4.5), 4.42-4.32 (m, 1H), 4.40 (s,1H), 3.05 (s, 3H), 2:86-2.68 (m, 2H), 1.81 (s, 3H), 1.55 (s, 3H), 1.47(s, 3H). Exact mass calculated for C₃₁H₃₇N₄O₅S (M+H)⁺ 577.2485, found577.2469.

EXAMPLE A583-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiiazolidine-4-carboxylicacid (ethyl-morpholino)-amide

White solid: ¹H NMR (DMSO-d₆) δ 9.81 (s, 1H), 9.40 (s, 1H), 8.18 (s,1H), 7.41-6.91 (m, 10H), 6.62 (d, J=7.7, 1H), 5.12 (q, J=9.3, 1H),4.44-4.35 (m, 3H), 4.08-2.78 (m, 12H), 2.81-2.67 (m, 2H), 1.88 (s, 3H),1.49 (s, 3H), 1.34 (s, 3H); Anal. (C₃₀H₄₀N₄O₆S.1.0H₂O.0.5TFA) calculatedC, (56.13), H, (6.45), N, (8.42), found C, (56.31), H, (6.55), N,(7.83). HRMS (ESI) m/z calcd for 585.2740, found 585.2747.

EXAMPLE A59(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.55 (t, J=5.8, 1H), 8.14 (d, J=8.4,1H), 7.29-7.11 (m, 8H), 6.94 (t, J=7.8, 1H), 6.77 (d, J=7.9, 1H), 6.54(d, J=7.4, 1H), 5.58 (d, J=8.2, 1H), 5.17 (d, J=9.2, 1H), 5.02 (d,J=9.2, 1H), 4.49-4.39 (m, 3H), 4.43 (s, 1H), 4.21 (dd, J=5.4, 15.3, 1H),2.83 (m, 1H), 2.71 (dd, J=13.5, 10.7, 1H), 2.20 (s, 3H), 1.51 (s, 3H),1.34 (s, 3H); HRMS (ESI) m/z calcd for C₃₂H₃₄F₂N₃O₇S (M+H)⁺ 642.2086,found 642.2099; Anal. Calcd for C₃₂H₃₃F₂N₃O₇S: C, 59.90; H, 5.18; N,6.55. Found: C, 60.01; H, 5.27; N, 6.29.

EXAMPLE A60(R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (1H-benzoimidazol-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.72 (t, J=5.5, 1H), 8.18 (d, J=8.3,1H), 7.33-7.11 (m, 10H), 6.95 (t, J=7.9, 1H), 6.79 (d, J=8.1, 1H), 6.57(d, J=7.1, 1H), 5.54 (d, J=6.6, 1H), 5.14 (d, J=9.3, 1H), 5.05 (d,J=9.3, 1H), 4.75 (m, 1H), 4.55-4.28 (m, 3H), 4.09 (dd, J=10.4, 5.2, 1H),2.86 (m, 1H), 2.72 (dd, J=13.5, 10.7, 1H), 1.82 (s, 3H), 1.53 (s, 3H),1.36 (s, 3H); HRMS (ESI) m/z calcd for C₃₂H₃₆N₅O₅S (M+H)⁺ 602.2437,found 602.2424; Anal. Calcd for C₃₂H₃₅N₅O₅S.0.4H₂O: C, 63.12; H, 5.93;N, 11.50. Found: C, 63.02; H, 5.99; N, 11.49.

EXAMPLE A61(R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (1H-indol-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 10.74 (s, 1H), 9.39 (s, 1H), 8.46 (t, J=4.9, 1H),8.17 (d, J=8.3, 1H), 7.45 (d, J=7.7, 1H), 7.37 (t, J=7.9, 2H), 7.26 (t,J=7.1, 2H), 7.18 (d, J=7.2, 1H), 7.10 (t, J=7.2, 1H), 6.99 (d, J=7.6,1H), 6.95 (d, J=7.5, 1H), 6.79 (d, J=7.7, 1H), 6.57 (d, J=7.1, 1H), 6.41(s, 1H), 5.49 (br s, 1H), 5.15 (d, J=9.1, 1H), 5.02 (d, J=9.2, 1H),4.69-4.39 (m, 4H), 2.86 (m, 1H), 2.74 (dd, J=13.5, 10.6, 1H), 1.83 (s,3H), 1.50 (s, 3H), 1.38 (s, 3H); HRMS (ESI) m/z calcd for C₃₃H₃₇N₄O₅S(M+H)⁺ 601.2485, found 605.2460.

EXAMPLE A62(R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (benzofuran-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.55 (t, J=5.5, 1H), 8.15 (d, J=8.3,1H), 7.52 (d, J=6.9, 1H), 7.51-7.36 (m, 3H), 7.28-7.18 (m, 5H), 6.96 (t,J=7.8, 1H), 6.78 (d, J=8.0, 1H), 6.61 (s, 1H), 6.55 (d, J=7.4, 1H), 5.42(br s, 1H), 5.12 (d, J=9.1, 1H), 5.00 (d, J=9.1, 1H), 4.48-4.39 (m, 5H),2.83 (m, 1H), 2.72 (dd, J=13.5, 10.7, 1H), 1.99 (s, 3H), 1.46 (s, 3H),1.27 (s, 3H); HRMS (ESI) m/z calcd for C₃₃H₃₆N₃O₆S (M+H)⁺ 602.2325,found 602.2326.

EXAMPLE A63(R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (1-methyl-1H-indol-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.39 (s, 1H), 8.46 (t, J=4.9, 1H), 8.17 (d, J=8.3,1H), 7.45 (d, J=7.7, 1H), 7.37 (t, J=7.9, 2H), 7.26 (t, J=7.1, 2H), 7.18(d, J=7.2, 1H), 7.10 (t, J=7.2, 1H), 6.99 (d, J=7.6, 1H), 6.95 (d,J=7.5, 1H), 6.79 (d, J=7.7, 1H), 6.57 (d, J=7.1, 1H), 6.41 (s, 1H), 5.49(br s, 1H), 5.15 (d, J=9.1, 1H), 5.02 (d, J=9.2, 1H), 4.66 (dd, J=15.5,6.4, 1H), 4.49 (s, 1H), 4.44 (m, 1H), 4.34 (dd, J=15.5, 4.2, 1H), 3.67(s, 3H), 2.86 (m, 1H), 2.74 (dd, J=13.5, 10.6, 1H), 1.83 (s, 3H), 1.50(s, 3H), 1.38 (s, 3H); HRMS (ESI) m/z calcd for C₃₄H₃₉N₄O₅S (M+H)⁺615.2641, found 615.2628; Anal. Calcd for C₃₄H₃₈N₄O₅S.0.3H₂O: C, 65.85;H, 6.27; N, 9.03. Found: C, 65.80; H, 6.23; N, 8.91.

EXAMPLE A64(R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (3-methyl-benzofuran-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.55 (t, J=5.5, 1H), 8.15 (d, J=8.3,1H), 7.52 (d, J=6.9, 1H, 7.51-7.36 (m, 3H), 7.28-7.18 (m, 5H), 6.96 (t,J=7.8, 1H), 6.78 (d, J=8.0, 1H), 6.55 (d, J=7.4, 1H), 5.42 (br s, 1H),5.12 (d, J=9.1, 1H), 5.00 (d, J=9.1, 1H), 4.48-4.39 (m, 5H), 2.83 (m,1H), 2.72 (dd, J=13.5, 10.7, 1H), 2.20 (s, 3H), 1.99 (s, 3H), 1.46 (s,3H), 1.27 (s, 3H); HRMS (ESI) m/z calcd for C₃₄H₃8N₃O₆S (M+H)⁺ 616.2481,found 616.2464; Anal. Calcd for C₃₄H₃₇N₃O₆S: C, 66.32; H, 6.06; N, 6.82.Found: C, 60.06; H, 6.04; N, 6.71.

EXAMPLE A64(R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (3-methyl-benzofuran-2-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.55 (t, J=5.5, 1H), 8.15 (d, J=8.3,1H), 7.52 (d, J=6.9, 1H, 7.51-7.36 (m, 3H), 7.28-7.18 (m, 5H), 6.96 (t,J=7.8, 1H), 6.78 (d, J=8.0, 1H), 6.55 (d, J=7.4, 1H), 5.42 (br s, 1H),5.12 (d, J=9.1, 1H), 5.00 (d, J=9.1, 1H), 4.48-4.39 (m, 5H), 2.83 (m,1H), 2.72 (dd, J=13.5, 10.7, 1H), 2.20 (s, 3H), 1.99 (s, 3H),

EXAMPLE A653-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiiazolidine-4-carboxylicacid (propyl-morpholino)-amide

White solid: ¹H NMR (DMSO-d₆) δ 9.81 (s, 1H), 9.40 (s, 1H), 8.18 (s,1H), 7.41-6.91 (m, 10H), 6.62 (d, J=7.7, 1H), 5.12 (dd, J=9.3, 1H),4.44-4.35 (m, 3H), 4.08-2.78 (m, 13H), 2.81-2.67 (m, 2H), 1.88 (s, 3H),1.49 (s, 3H), 1.34 (s, 3H); Anal. (C₃₁H₄₂N₄O₆S.0.18H₂O) calculated C,(51.56), H, (5.53), N, (9.36), found C, (52.05), H, (5.95), N, (6.51).HRMS (ESI) m/z calcd for 599.2902, found 599.2903.

Amides of the general structure 3 (synthesized in the same manor as inthe Methods A section) are coupled to boc-protected acid 15, and exposedto methane sulfonic acid to yield amines 16. Subjecting amines 16 to thereaction conditions depicted yielded a series of amides 17, carbamates18, and ureas 19.Synthesis of Amines of the General Type 16.

The title compound was prepared as follows.(R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1(1.95 g, 7.47 mmol) was dissolved in EtOAc (25 mL) and cooled to 0° C.Diphenyl chlorophosphate (1.71 mL, 8.23 mmol) was added followed by TEA(1.14 mL, 8.23 mmol). The reaction was stirred at 0° C. for 1 h, andtreated with (S)-Cyclohex-2-enylamine (0.8 g, 8.23 mmol). The reactionmixture was stirred at room temperature overnight, then partitionedbetween 1N HCl (25 mL) and EtOAc (30 mL). The organic layer was washedwith saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated to ayellow oil. The resulting oil (2.54 g, 7.47 mmol) was dissolved in EtOAc(30 mL) and then cooled to 0° C. Methanesulfonic acid (2.27 mL, 33.62mmol) was added and the solution was stirred at 0° C. for 15 minutes,then at room temperature for 4 h. The mixture was re-cooled to 0° C. andquenched with 10% Na₂CO₃ (30 mL) then extracted with EtOAc (30 mL).Organic layer was washed with brine, dried over Na₂SO₄ and concentratedin vacuo to give a yellow oil 3. The resulting yellow oil (1.86 g, 7.74mmol) was dissolved in EtOAc (77 mL). BOC-AHPBA 4 (2.29 g, 7.74 mmol)was added followed by HOBt (1.05 g, 7.74 mmol). The mixture was stirredat room temperature 1 h, then cooled to 0° C. DCC (1.60 g, 7.74 mmol)was slowly added as solution in EtOAc (30 mL). The mixture was allowedto gradually warm to room temperature and stirred overnight. The mixturewas filtered and the filtrate was washed with 1N HCl (40 mL), saturatedNaHCO₃ (40 mL), brine (40 mL), dried over Na₂SO₄ and concentrated togive a crude white solid (contaminated with DCU). The DCU was removed byflash chromatography (30% to 50% EtOAc in hexanes) to provide a whitesolid (4 g, 7.73 mmol), which was dissolved in EtOAc (30 mL) and thencooled to 0° C. Methanesulfonic acid (2.35 mL, 34.76 mmol) was added andthe solution was stirred at 0° C. for 15 minutes, then at roomtemperature for 3 h. The mixture was re-cooled to 0° C. and quenchedwith 10% Na₂CO₃ (35 mL) then extracted with EtOAc (30 mL). Organic layerwas washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive a material which was recrystalized from 60% EtOAc in hexanes toprovide B1 (2.41 g, 80%) as a white solid. ¹H NMR (DMSO-d₆) δ 8.21 (d,J=8.1, 1H), 7.31-7.17 (m, 5H), 5.80 (d, J=5.6, 1H), 5.52-5.48 (m, 2H),5.30-5.25 (m, 2H), 4.89 (s, 2H), 4.26 (s, 1H), 4.21-4.00 (m, 3H),3.15-2.70 (m, 2H), 2.50-2.00 (m, 2H), 2.00-1.00 (m, 4H), 1.49 (s,-3H),1.31 (s, 3H); Anal. Calcd for C₂₂H₃₁N₃O₃S: C, 63.28; H, 7.48; N, 10.06.Found: C, 63.40; H, 7.20; N, 9.98.

The following amines 16b-k were prepared by the specific method outlinedabove using the requisite amine.

¹H NMR (DMSO-d₆) δ 8.36 (t, J=6.0, 1H), 7.36-7.14 (m, 5H), 5.70 (m, 1H),5.34 (s br, 1H), 5.12 (d, J=17.0, 1H), 4.96-4.88 (m, 3H), 4.34 (s, 1H),4.10 (d, J=7.0, 1H), 3.80-3.55 (m, 2H), 3.06 (d, J=13.0, 1H), 2.87 (t,J=9.0, 1H), 2.38 (dd, J=13.0, 10.0, 1H), 1.52 (s, 3H), 1.33 (s, 3H).

¹H NMR (DMSO-d₆) δ 8.69 (t, J=5.3, 1H), 7.34-7.14 (m, 5H), 5.34 (s br,1H), 4.90 (s, 2H), 4.29 (s, 1H), 4.08 (d, J=7.0, 1H), 3.90-3.70 (m, 2H),3.07 (dd, J=13.4, 2.5, 1H), 2.96 (t, J=2.6, 1H), 2.88 (ddd, J=9.8, 8.0,2.8, 1H), 2.37 (dd, J=13.2, 9.9, 1H), 1.50 (s, 3H), 1.32 (s, 3H).

¹H NMR (DMSO-d₆) δ 8.74 (t, J=5.4, 1H), 7.36 (m, 1H), 7.34-7.14 (m, 5H),6.24 (m, 1H), 6.16 (d, J=3.3, 1H), 5.32 (s br, 1H), 4.90 (s, 2H), 4.32(s, 1H), 4.30-4.10 (m, 2H), 4.07 (d, J=9.0, 1H), 3.09 (dd, J=13.1, 2.6,1H), 2.80 (ddd, J=10.0, 8.0,2.7, 1H), 2.33 (dd, J=13.1, 10.0, 1H), 1.50(s, 3H), 1.28 (s, 3H).

¹H NMR (DMSO-d₆) δ 8.36 (t, J=5.4, 1H), 7.33-7.15 (m, 5H), 5.30 (s br,1H), 4.90 (s, 2H), 4.30 (s, 1H), 4.09 (d, J=7.9, 1H), 3.06 (dd, J=13.2,2.0, 1H), 3.02-2.77 (m, 3H), 2.47 (dd, J=13.4, 10.1, 1H), 1.50 (s, 3H),1.34 (s, 3H), 0.80 (m, 1H), 0.28 (m, 2H), 0.06 (m, 2H).

¹H NMR (DMSO-d₆) δ 8.59 (d, J=7.3, 1H), 7.29-7.20 (m, 5H), 7.04 (d,J=6.8, 1H), 6.89 (d, J=7.2, 1H), 6.76-6.72 (m, 1H), 6.53-6.46 (m, 1H),5.32 (d, J=-5.9, 1H), 4.89 (s, 2H), 4.89-4.80 (m, 1H), 4.24 (s, 1H),4.17-3.90 (m, 2H), 3.08-3.04 (m, 2H), 2.20-1.70 (m, 4H), 1.52 (s, 3H),1.35 (s, 3H); Anal. Calcd for C₂₅H₃₁N₃O₄S: C, 63.94; H, 6.65; N, 8.95.Found: C, 63.76; H, 6.60; N, 8.98.

¹H NMR (DMSO-d₆) δ 8.37 (d, J=7.3, 1H), 7.30-6.66 (m, 9H), 5.29 (d,J=8.2, 1H), 4.86 (s, 2H), 4.86-4.80 (m, 1H), 4.23 (s, 1H), 4.05-3.97 (m,1H), 3.08-3.04 (m, 1H), 2.70-2.40 (m, 4H), 2.20-2.00 (m, 2H), 1.70-1.55(m, 4H), 1.52 (s, 3H), 1.36 (s, 3H); Anal. Calcd for C₂₆H₃₃N₃O₃S: C,66.78; H, 7.11; N, 8.99. Found: C, 66.90; H, 7.01; N, 8.98.

¹H NMR (DMSO-d₆) δ 8.47 (d, J=8.6, 1H), 7.28-6.82 (m, 9H), 5.33 (d,J=5.9, 1H), 5.25-5.19 (m, 1H), 4.91 (d, J=9.2, 1H), 4.85 (d, J=9.2, 1H),4.29 (s, 1H), 4.03 (d, J=8.1, 1H), 3.08-3.05 (m, 1H), 2.77-2.60 (m, 2H),2.30-2.10 (m, 2H), 1.70-1.50 (m, 2H), 1.52 (s, 3H), 1.36 (s, 3H); Anal.Calcd for C₂₅H₃₁N₃O₃S: C, 66.20; H, 6.89; N, 9.26. Found: C, 66.35; H,7.01; N, 8.98.

¹H NMR (DMSO-d₆) δ 8.35 (t, J=5.7, 1H), 7.31-7.16 (m, 5H), 5.24 (d,J=8.1, 1H), 4.92 (d, J=9.2, 1H), 4.88 (d, J=9.2, 1H), 4.31 (s, 1H), 4.09(m, 1H), 3.83-3.51 (m, 2H), 3.42-3.31 (m, 1H), 3.23-3.07 (m, 2H),2.99-2.91 (m, 1H), 2.86-2.79 (m, 1H), 2.34 (dd, J=13.0, 10.1, 1H),1.80-1.42 (m, 6H), 1.50 (s, 3H), 1.31 (s, 3H).

¹H NMR (DMSO-d₆) δ 8.13 (t, J=5.4, 1H), 7.35-7.15 (m, 5H), 5.28 (d,J=8.1, 1H), 4.79 (m, 2H), 4.27 (s, 1H), 4.07 (t, J=7.1, 1H), 3.10-2.71(m, 4H), 2.37 (dd, J=13.2, 9.9, 1H), 1.49 (s, 3H), 1.34 (m, 2H), 1.33(s, 3H), 0.77 (t, J=7.4, 3H).

Isolated yield: 84%; MS (APCI, m/z): 461, 463 (M+H).

Isolated yield: 93%; MS (APCI, m/z): 464 (M+H).

Isolated yield: 86%; MS (APCI, m/z): 496 (M+H).

Isolated yield: 87%. MS-APCI (m/z+): 458.

Isolated yield: 45%. MS-APCI (m/z+): 341, 429.

Synthesis of Final Products of the General Type 17, 18 and 19 from16a-k, General Methods:

Carbamate formation #1—The corresponding amine, of general structure 16,triethylamine (2 eq.) and chloroformate (1.1-1.2 eq.) were taken indichloromethane and stirred at room temperature under nitrogen. (1.5 hrto overnight). The solvent was then removed in vacuo and the resultingresidue subjected to flash silica gel chromatography or preparative HPLCto afford the desired product.

Carbamate formation #2—The corresponding alcohol was treated withphosgene (1.7 eq.) in toluene followed by diisopropylethylamine (1.1eq.) and the amine of general structure The solvent was then removed invacuo and the resulting residue subjected to flash silica gelchromatography or preparative HPLC to afford the desired product.

Amide formation—To a solution of acid, amine 16 and HOBT in CH₂Cl₂ wasadded EDC and the solution stirred overnight at room temperature. Thesolution was concentrated in vacuo and the residue dissolved in ethylacetate and a small portion of water. The solution was washed withsaturated NH₄Cl or 0.5N HCl (2×), saturated NaHCO₃ (2×), brine (1×),dried with MgSO₄ and concentrated in vacuo. The resulting residuesubjected to flash silica gel chromatography or preparative HPLC toafford the desired product.

Urea formation #1—The corresponding amine and isocyanate (1.1-1.2 eq.)were taken in dichloromethane and stirred at room temperature undernitrogen. (1.5 hr to overnight). The solvent was then removed in vacuoand the resulting residue subjected to flash silica gel chromatographyor preparative HPLC to afford the desired product.

Urea formation #2—The corresponding amine was dissolved in CH₂Cl₂ andtreated with diisopropylethylamine (1.5 eq.) and phosgene (1 eq., 20%soln. in toluene) at −78° C. The resulting solution was warmed to roomtemperature and treated with the amine of general structure 16. Theresulting residue subjected to flash silica gel chromatography orpreparative HPLC to afford the desired product.

Specific Carbamate Synthesis EXAMPLE B1{1-Benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid tetrahydropfuran-3-yl-ester

(S)-(+)-3-Hydroxytetrahydrofuran (0.11 mL, 1.37 mmol) was dissolved intoluene (1 mL) and cooled to 0° C. with magnetic stirring. To this wasadded Phosgene as a 20% solution in toluene (1.2 mL, 2.34 mmol). Theresulting solution was stirred for 24 h at 23° C. then concentrated. Theresidue was dissolved in dry THF (3 mL) and treated withDiisopropylethylamine (0.25 mL, 1.40 mmol). 16c was added as a slurry inTHF (0.3 g, 0.73 mmol) and resulting amber solution was stirred at 23°C. for 3 h. The solution was diluted with EtOAc (10 mL) and washed with10% citric acid (25 mL) dried over Na₂SO₄, filtered, and concentrated toa white solid.

¹H NMR (CDCl₃) δ 7.23-7.09 (m, 9H), 6.79 (s br, 1H), 5.90 (s br, 1H),5.16-3.63 (m, 17H), 1.55 (s, 3H), 1.50 (s, 3H), 1.45 (s, 3H); HRMS (ESI)m/z calcd for C₂₉H₃₇N₃O₆SNa (M+Na)⁺ 578.2301, found 578.2288; Anal.Calcd for C₂₉H₃₇N₃O₆S.1H₂O: C, 60.71; H, 6.85; N, 7.32. Found: C, 60.97;H, 6.47; N, 6.91.

Specific Amide Synthesis EXAMPLE B21,2,3,4-Tetrahydro-quinoline-5-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

The amine 16c (0.21 g, 0.48 mmol) and1,2,3,4-Tetrahydroquinoline-5-carboxylic acid (0.085 g, 0.48 mmol) weredissolved in dry CH₂Cl₂ (5 mL) at 23° C. with magnetic stirring. Thesolution was treated sequentially with EDC (0.18 g, 0.96 mmol), HOBt(0.13 g, 0.96 mmol), and Triethylamine (0.14 mL, 0.96 mmol). The resultwas stirred for 24 h and then poured into H₂O (25 mL). The mixture wasextracted with EtOAc (2×25 mL). The combined organics were washedsequentially with saturated NaHCO₃ (1×50 mL), 0.5N HCl (1×50 mL), andH₂O (1×50 mL). The result was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash column chromatography(40%-60% EtOAc in hexanes) to yield the title compound as a pale yellowsolid (0.21 g, 72%).

¹H NMR (DMSO-d₆) δ 8.32 (t, J=5.1, 1H), 8.04 (d, J=8.4, 1 H), 7.33-7.10(m, 9H), 6.79 (t, J=7.7, 1H), 6.41 (d, J=8.1, 1H), 6.22 (d, J=7.3, 1H),5.71 (s br, 1H), 5.46 (d, J=6.8, 1H), 5.14 (d, J=9.2, 1H), 5.01 (d,J=9.2, 1H), 4.48-4.37 (m, 4H), 4.11 (dd, J=15.0, 4.8, 1H), 3.07 (m, 2H),2.84-2.67 (m, 2H), 2.32-2.26 (m, 2H), 2.26 (s, 3H), 1.59 (m, 2H), 1.49(s, 3H), 1.35 (s, 3H); HRMS (ESI) m/z calcd for C₃₄H₄₀N₄O₄SNa (M+Na)⁺623.2662, found 623.2669; Anal. Calcd for C₃₄H₄₀N₄O₄S: C, 66.97; H,6.78; N, 9.18. Found: C, 66.97; H, 6.73; N, 9.12.

Specific Urea Synthesis EXAMPLE B33-(2-hydroxy-3-{[1-(3-hydroxy-pyrrolidin-yl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid-2-methyl-benzylamide

(R)-Pyrrolidin-3-ol (0.21 g, 2.40 mmol) was dissolved in dry CH₂Cl₂ (15mL) and cooled to −78° C. under argon with magnetic stirring. To thissolution was added Diisopropylethylamine (0.63 mL, 3.63 mmol) followedby Phosgene as a 20% solution in toluene (1.2 mL, 2.40 mmol). Theresulting yellow solution was stirred for 20 min at −78° C. then allowedto warm to room temperature. The solution was concentrated andre-dissolved in dry CH₂Cl₂ (5 mL) and THF (5 mL). To this was addedDiisopropylethylamine (0.31 mL, 1.81 mmol) followed by 16c. The resultwas stirred for 16 h at 23° C. then diluted with EtOAc (50 mL). Themixture was washed sequentially with 10% citric acid (1×50 mL),saturated NaHCO₃ (1×50 mL), H₂O (1×50 mL). The organics were dried overNa₂SO₄, filtered, and concentrated. The residue was purified by flashcolumn chromatography (5% MeOH in EtOAc) to yield the title compound(0.12 g, 18%) as a white foam.

¹H NMR (DMSO-d₆) δ 8.38 (t, J=5.7, 1H), 7.34-7.09 (m, 10H), 5.99 (d,J=8.3, 1H), 5.04 (d, J=9.5, 1H), 4.96 (d, J=9.5, 1H), 4.49 (s, 1H),4.48-4.38 (m, 3H), 4.22-3.83 (m, 4H), 3.29-3.04 (m, 3H), 2.77-2.70 (m,2H), 2.28 (s, 3H), 1.52 (s, 3H), 1.32 (s, 3H), 1.82-1.69 (m, 2H); HRMS(ESI) m/z calcd for C₂₉H₃₈N₄O₅SNa (M+Na)⁺ 577.2455, found 577.2440;Anal. Calcd for C₂₉H₃₈N₄O₅S.2H₂O: C, 58:96; H, 7.17; N, 9.48; S, 5.43.Found: C, 58.90; H, 6.40; N, 9.23; S, 5.24.

The following examples were prepared by the corresponding specificmethod outlined above using the requisite P2 fragment.

EXAMPLE B43-{2-Hydroxy-4-phenyl-3-[2-(2H-[1,2,4-t]triazol-3-ylsufanyl)-ethanoylamino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid-2-methyl-benzylamide

¹H NMR (DMSO-d₆) δ 14.00 (s br, 1H), 8.54 (s br, 1H), 8.35 (t, J=5.7,1H), 8.30 (s br, 1H), 7.32-7.06 (m, 10H), 4.98 (d, J=9.2, 1H), 4.92 (d,J=9.2, 1H), 4.50 (s, 1H), 4.43-4.36 (m, 2H), 4.12 (m, 2H), 3.77 (s br,2H), 2.76-2.58 (m, 2H), 2.26 (s, 3H), 1.50 (s, 3H), 1.32 (s, 3H); HRMS(ESI) m/z calcd for C₂₈H₃₄N₆O₄S₂Na (M+Na)⁺ 605.1975, found 605.1988;Anal. Calcd for C₂₈H₃₄N₆O₄S₂.0.25H₂O: C, 57.27; H, 5.92; N, 14.31; S,10.92. Found: C, 57.21; H, 5.97; N, 14.10; S, 10.71.

EXAMPLE B5{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid (R)-2-isopropyl-tetrahydro-thiophen-3-yl ester

¹H NMR (DMSO-d₆) δ 8.38 (s br, 2H), 7.42-7.09 (m, 9H), 5.12 (s, 1H),4.99 (s, 2H), 4.52-3.80 (m, 5H), 3.19-2.79 (m, 6H), 2.29 (s, 3H),1.99-1.71 (m, 3H), 1.51 (s, 3H), 1.39 (s, 3H), 0.99 (m, 6H); Anal. Calcdfor C₃₂H₄₃N₃O₅S₂: C, 62.61; H, 7.06; N, 6.85. Found: C, 62.45; H, 6.84;N, 7.04.

EXAMPLE B6 2,3-Dihydro-1H-indole-4-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Pale yellow solid; IR (neat, cm⁻¹) 3417, 1644, 1529, 1453, 1114; ¹H NMR(DMSO-d₆) δ 8.35 (t, J=5.1, 1H), 8.06 (d, J=8.6, 1H), 7.34-7.11 (m, 9H),6.91 (t, J=7.7, 1H), 6.78 (d, J=5.5, 1H), 6.70 (d, J=7.5, 1H), 6.53 (d,J=7.7, 1H), 5.58 (s, 1H), 5.10 (d, J=9.2, 1H), 5.00 (d, J=9.2, 1H),4.51-4.36 (m, 4H), 4.13 (dd, J=15.0, 4.6, 1H), 3.34-3.29 (m, 2H),2.80-2.00 (m, 4H), 2.25 (s, 3H), 1.50 (s, 3H), 1.35 (s, 3H); HRMS (ESI)m/z calcd for C₃₃H₃₈N₄O₄SNa (M+Na)⁺ 609.2506, found 609.2485.

EXAMPLE B7(R)-3-{(2S,3S)-3-[2-(2,6-Dimethylphenoxy)-ethanoylamino]-2-hydroxy-4-phenyl-butanoyl}-5,5-dimethylthiazolidine-4-carboxylicacid 2-methyl-benzylamide

EXAMPLE B8 1H-Indole-4-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

White solid; IR (neat, cm⁻¹) 3422, 1642, 1520, 1349, 1114; ¹H NMR(DMSO-d₆) δ 11.24 (s, 1H), 8.36 (t, J=6.1, 1H), 8.18 (d, J=8.2, 1H),7.50 (d, J=8.1, 1H), 7.51-7.06 (m, 12H), 6.71 (s, 1H), 5.48 (d, J=6.4,1H), 5.11 (d, J=9.3, 1H), 5.04 (d, J=9.3, 1H), 4.58-4.49 (m, 3H), 4.39(dd, J=15.2, 6.6, 1H), 4.14 (dd, J=15.2, 4.9, 1H), 2.86 (m, 2H), 2.25(s, 3H), 1.51 (s, 3H), 1.35 (s, 3H); HRMS (ESI) m/z calcd forC₃₃H₃₆N₄O₄SNa (M+Na)⁺ 607.2349, found 607.2350.

EXAMPLE B9 1H-Indazle-4-carboxylic acid{1-benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

¹H NMR (DMSO-d₆) δ 13.18 (s, 1H), 8.46 (d, J=8.2, 1H), 8.35 (t, J=5.6,1H), 8.20 (s, 1H), 7.68-7.06 (m, 12H), 5.53 (d, J=6.6, 1H), 5.13 (d,J=9.1, 1H), 5.06 (d, J=9.1, 1H), 4.61-4.54 (m, 2H), 4.51 (s, 1H), 4.40(dd, J=14.9, 6.2, 1H), 4.16 (dd, J=14.9, 4.7, 1H), 2.91-2.89 (m, 2H),2.51 (s, 3H), 1.53 (s, 3H), 1.31 (s, 3H); HRMS (ESI) m/z calcd forC₃₂H₃₅N₅O₄SNa (M+Na)⁺ 608.2302, found 608.2273; Anal. Calcd forC₃₂H₃₅N₅O₄S.0.35H₂O: C, 64.92; H, 6.08; N, 11.83; S, 5.42. Found: C,65.15; H, 6.21; N, 11.44; S, 5.13.

EXAMPLE B10{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid prop-2-ynyl ester

Isolated yield: 83%; 1-H NMR (400 MHz, dmso-d₆): δ 8.30 (t, 1H), 7.48(d, 1H), 7.0-7.3 (m, 10H), 5.35 (d, 1H), 4.96 (q, 2H), 4.48-4.31 (m,5H), 4.14 (dd, 1H), 3.87 (m, 1H), 3.44 (s, 1H), 2.7 (dd, 1H), 2.61 (t,1H), 2.26 (s, 3H), 1.48 (s, 3H), 1.35 (s, 3H); IR (KBr in cm−1): 3302,1711, 1643, 1528, 1237, 1047; MS (APCI, m/z): 524 (M+H):C28H33N3O5S1.0.21H2O Calculated: C, 63.76, H, 6.39, N, 7.97, Observed:C, 64.22, H, 6.35, N, 8.02; HPLC: Rf (min.) 20.177; Purity: 99%.

EXAMPLE B11{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid allyl ester

Isolated yield: 83%; 1H-NMR (400 MHz, dmso-d₆): δ 8.30 (t, 1H),7.04-7.35 (m, 10H), 5.7-5.83 (m, 1H), 5.3 (d, 1H), 5.09 (d, 1H), 5. 14(d, 1H), 4.96 (q, 2H), 4.3 (s, 1H), 4.3-4.43 (m, 4H), 4.13 (dd, 1H),3.87 (m, 1H), 2.74 (dd, 1H), 2.61 (dd, 1H), 2.26 (s, 3H), 1.48 (s, 3H),1.30 (s, 3H); IR (KBr in cm−1): 3324, 1691, 1645, 1530, 1238, 1041; MS(APCI, m/z): 526 (M+H), 468; C28H35N3O5S1.0.35H2O Calculated: C, 63.22,H, 6.76, N, 7.90, Observed: C, 663.98, H, 6.71, N, 7.99; HPLC: Rf (min.)20.97; Purity: 98%.

EXAMPLE B12(R)-3-[(2S,3S)-2-Hydroxy-3-(2-methyl-butyrylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 75%; 1H-NMR (400 MHz, dmso-d₆): δ 8.37 (q, 1H), 7.71 (d,1H), 7.04-7.37 (m, 9H), 5.24 (brd, 1H), 5.11 (t, 1H), 5.04 (dd, 1H),4.5-4.28 (m, 3H), 4.15 (m, 2H), 2.75-2.54 (m, 2H), 2.28 (s, 3H), 2.11(m, 1H), 1.5 (s, 3H), 1.27 (s, 3H), 1.02-1.24 (m, 2H), 0.93 (d)+0.7(m)+0.41 (t) 6H; IR (KBr in cm−1): 3311, 2966, 1642, 1530; MS (APCI,m/z): 526 (M+H), 480, 265; C29H39N3O4S1.0.38H2O Calculated: C, 65.41; H,7.53; N, 7.89, Observed: C, 66.26, H, 7.48, N, 7.99; HPLC: Rf (min.)20.68; Purity: 100%.

EXAMPLE B13(R)-3-[(2S,3S)-3-(3-Allyl-ureido)-2-hydroxy-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 65%; 1H-NMR (400 MHz, dmso-d₆): δ 8.35 (t, 1H),7.35-7.04 (m, 10H), 6.13 (d, 1H), 5.96 (t, 1H), 5.70 (m, 1H), 5.13-4.87(m, 5H), 4.5-4.35 (m, 2H), 4.17 (dd, 1H), 4.04 (t, 1H), 3.52 (m, 2H),2.22 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3H); MS (APCI, m/z): 541 (M+H),442, 396, 277; HPLC: Rf (min.) 21.05; Purity: >95%.

EXAMPLE B14{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid but-3-enyl ester

Isolated yield: 81%; 1H-NMR (400 MHz, dmso-d₆): δ 8.26 (t, 1H), 7.0-7.27(m, 10H) 5.7-5.56 (m, 1H), 5.27 (d, 1H), 4.83-5.04 (m, 4H), 4.4 (s, 1H),4.35 (m, 2H), 4.13 (dd, 1H), 3.65-3.87 (m, 2H), 2.65 (d, 1H), 2.52 (m,1H), 2.22 (s, 311), 2.17 (m, 2H), 1.44 (s, 3H), 1.26 (s, 3H); MS (APCI,m/z): 540 (M+H), 468; HPLC: Rf (min.) 21.31; Purity: 96%.

EXAMPLE B153-[(S)-3-(Cyclopropanecarbonyl-amino)-2-hydroxy-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 78%; 1H-NMR (400 MHz, dmso-d₆): δ 8.35 (t, 1H), 8.26 (d,1H), 7.0-7.26 (m, 10H), 5.174 (d, 1H), 5.0 (d, 1H), 4.87 (d, 1H), 4.44(s, 1H), 4.3-4.44 (m, 2H), 4.17-4.04 (m, 2H), 2.30-2.70 (m, 2H), 1.52(m, 1H), 1.44 (s, 3H), 1.30 (s, 3H), 0.52 (m, 2H), 0.44 (m, 2H); MS(APCI, m/z): 510 (M+H), 265; HPLC: Rf (min.) 19.857; Purity: 94%.

EXAMPLE B16{(S)-1-Benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid isopropyl ester

Isolated yield: 81%; 1H-NMR (400 MHz, dmso-d₆): δ 8.26 (t, 1H), 7.0-7.30(m, 10H), 5.26 (brs, 1H), 4.91 (q, 2H), 4.35-4.13 (m, 2H), 4.13 (dd,1H), 4.83 (t, 1H), 3.7 (q, 1H), 2.66 (dd, 1H), 2.52 (t, H), 2.2 (s, 3H),1.44 (s, 3H), 1.26 (s, 3H), 0.74 (t, 6H); MS (APCI, m/z): 528 (M+H),468; HPLC: Rf (min.) 21.127; Purity: 98%.

EXAMPLE B173-[(S)-2-Hydroxy-3-(3-isopropyl-ureido)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 81%; 1H-NMR (400 MHz, dmso-d₆): δ 8.35 (t, 1H), 7.0-7.32(m, 10H), 5.87 (d, 1H), 5.7 (d, 1H), 5.17 (d, 1H), 5.03 (d, 1H), 4.91(d, 1H), 4.48-4.3 (m, 2H), 4.44 (s, 1H), 4.17 (dd, 1H), 4.0 (m, 1H),3.52 (m, 1H), 2.65 (dd, 1H), 2.22 (s, 3H), 1.48 (s, 3H), 1.35 (s, 3H),0.91 (d, 3H), 0.83 (d, 3H); MS (APCI, m/z): 527 (M+H), 442, 396, 263;HPLC: Rf (min.) 19.94; Purity: 95%.

EXAMPLE B18(R)-3-((2S,3S)-2-Hydroxy-3-pent-4-ynoylamino-4-phenyl-butyryl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 79%; 1H-NMR (400 MHz, dmso-d₆): δ 8.35 (t, 1H), 8.08 (d,1H), 7.35-7.0 (m, 10H), 5.26 (d, 1H), 5.04 (d, 1H), 5.87 (d, 1H), 4.48(s, 1H), 4.38 (m, 2H), 4.15 (m, 2H), 2.74-2.52 (m, 2H), 2.22 (s, 3H),2.17 (m, 4H), 1.48 (s, 3H), 1.30 (s, 3H); IR (KBr in cm−1): 3294, 1642,1530, 744; MS (APCI, m/z): 522 (M+H), 476, 265; C30H36N4O4S1.2.44H2OCalculated: C, 60.80, H, 6.95, N, 9.45, Observed: C, 65.67, H, 6.61, N,10.21; HPLC: Rf (min.) 19.787; Purity: 100%.

EXAMPLE B19(R)-3-[(2S,3S)-2-Hydroxy-4-phenyl-3-(3,3,3-trifluoropropionylamino)-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 72%; 1H-NMR (400 MHz, dmso-d₆): δ 8.48 (d, 1H), 8.38 (t,1H), 7.35-7.04 (m, 10H), 5.35 (d, 1H), 5.0 (d, 1H), 4.92 (d, 1H), 4.48(s, 1H), 4.38 (m, 2H), 4.17 (m, 2H), 3.14 (m, 2H), 2.7 (d, 1H), 2.6 (t,1H), 2.26 (s, 3H), 1.48 (s, 3H), 1.35 (s, 3H); IR (KBr in cm−1): 3305,1649, 1534, 1239, 1110, 743; MS (APCI, m/z): 552 (M+H), 431, 265;C27H₃₂N304S1.F3.0.41H2O Calculated: C, 58.01, H, 5.92, N, 7.52,Observed: C, 58.79, H, 5.85, N, 7.62; HPLC: Rf (min.) 20.319; Purity:100%.

EXAMPLE B20(R)-3-((2S,3S)-3-Butyrylamino-2-hydroxy-4-phenyl-butyryl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 72%; 1H-NMR (400 MHz, dmso-d₆): δ 8.35 (t, 1H), 7.96 (d,1H), 7.35-7.04 (m, 10H), 5.22 (d, 1H), 5.09 (d, 1H), 4.91 (d, 1H), 4.48(s, 1H), 4.38 (m, 2H), 4.17 (m, 2H), 2.67 (d, 1H), 2.56 (t, 1H), 2.26(s, 3H), 1.91 (t, 2H), 1.48 (s, 3H), 1.30 (s+m, 5H), 0.65 (t, 3H); IR(KBr in cm−1): 3308, 2967, 1641, 1534, 743; MS (APCI, m/z): 512 (M+H),466, 265; C28H35N3O4S1.0.48H2O Calculated: C, 65.16, H, 7.03, N, 7.71,Observed: C, 65.16, H, 7.09, N, 8.44; HPLC: Rf (min.) 20.070; Purity:95%.

EXAMPLE B21 2,3-Dihydro-1H-indole-4-carboxylic acid[(1S,2S)-3-((R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl)-1-benzyl-2-hydroxy-3-oxo-propyl]-amide

Beige solid; ¹H NMR (DMSO-d₆) δ 8.09 (t, J=5.7, 1H), 8.00 (d, J=8.6,1H), 7.70 (d, J=7.7, 1H), 7.34-7.11 (m, 6H), 6.91 (t, J=7.9, 1H), 6.68(d, J=8.1, 1H), 5.80-5.71 (m, 1H), 5.58 (s, 1H), 5.44 (d, J=7.0, 1H),5.23-5.01 (m, 4H), 4.47-4.39 (m, 4H), 3.73-3.61 (m, 2H), 2.99-2.81 (m,4H), 1.50 (s, 3H), 1.35 (s, 3H); HRMS (ESI) m/z calcd for C₂₈H₃₄N₄O₄SNa(M+Na)⁺ 545.219, found 545.2205.

EXAMPLE B22[(1S,2S)-3-((R)-4-Allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl)-1-benzyl-2-hydroxy-3-oxo-propyl]-carbamicacid (S)-(tetrahydro-furan-3-yl)ester

White solid; ¹H NMR (DMSO-d₆) δ 8.06 (t, J=5.9, 1H), 7.27-7.12 (m, 6),5.76 (m, 1H), 5.39 (d, J=7.1, 1H), 5.19 (dd, J=17.2, 1.7, 1H), 5.03-4.90(m, 4H), 4.39-4.35 (m, 2H), 3.88 (m, 1H), 3.76-3.58 (m, 5H), 3.42 (d,J=10.4, 1H), 2.75-2.55 (m, 2H), 2.03 (m, 1H), 1.80 (m, 1H), 1.49 (s,3H), 1.34 (s, 3H); HRMS (ESI) m/z calcd for C₂₄H₃₃N₃O₆SNa (M+Na)⁺514.1982, found 514.1967.

EXAMPLE B23(R)-3-{(2S,3S)-3-[2-(2,6-Dimethyl-phenoxy)-ethanoylamino]-2-hydroxy-4-phenyl-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

White solid; IR (neat, cm⁻¹) 3418, 1651, 1532, 1454, 1372, 1264, 1195;¹H NMR (DMSO-d₆) δ 8.15 (t, J=5.7, 1H), 8.10 (d, J=8.8, 1H), 7.32-7.13(m, 5H), 7.00-6.89 (m, 3H), 5.83-5.71 (m, 1H), 5.48 (d, J=6.8, 1H), 5.21(dd, J=17.2, 1.8, 1H), 5.03-4.91 (m, 3H), 4.49-4.36 (m, 3H), 4.16 (d,J=14.1, 1H), 3.98 (d, J=14.1, 1H), 3.72 (m, 2H), 2.79-2.76 (m, 2H), 2.13(s, 6H), 1.50 (s, 3H), 1.36 (s, 3H); HRMS (ESI) m/z calcd forC₂₉H₃₇N₃O₅SNa (M+Na)⁺ 562.2346, found 562.2324.

EXAMPLE B24 1-H-indazole-4-carboxylic acid[3-(4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl)-1-benzyl-2-hydroxy-3-oxo-propyl]-amide

¹H NMR (DMSO-d₆) δ 13.18 (s, 1H), 8.42 (d, J=8.2, 1H), 8.19 (s, 1H),8.10 (t, J=5.7, 1H), 7.68-7.11 (m, 8H), 5.81-5.72 (m, 1H), 5.52 (d,J=6.8, 1H), 5.24-4.83 (m, 4H), 4.57 (m, 2H), 4.42 (s, 1H), 3.74-3.66 (m,2H), 2.90 (m, 2H), 1.53 (s, 3H), 1.37 (s, 3H); Anal. Calcd forC₂₇H₃₁N₅O₄S.0.25H₂O: C, 61.63; H, 6.04; N, 13.31; S, 6.09. Found: C,61.63; H, 6.09; N, 12.95; S, 5.95.

EXAMPLE B25(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[2-(1H-[1,2,4]triazol-3-ylsulfanyl)-ethanoylamino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

EXAMPLE B26{(1S,2S)-1-Benzyl-3-[(R)-4-(cyclopropylmethyl-carbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid (S)-(tetrahydro-furan-3-yl)ester

White solid; ¹H NMR (DMSO-d₆) δ 7.99 (t, J=5.7, 1H), 7.28-7.07 (m, 6H),5.32 (d, J=7.3, 1H), 4.96-4.92 (m, 3H), 4.38 (s, 1H), 3.90 (m, 1H),3.76-3.54 (m, 4H), 3.41 (d, J=10.4, 1H), 3.04-2.92 (m, 2H), 2.73-2.54(m, 2H), 2.03 (m, 1H), 1.83 (m, 1H), 1.49 (s, 3H), 1.36 (s, 3H), 0.88(m, 1H), 0.35 (m, 2H), 0.15 (m, 2H); HRMS (ESI) m/z calcd forC₂₅H₃₅N₃O₆SNa (M+Na)⁺ 528.2139, found 528.2121.

EXAMPLE B27(R)-3-{(2S,3S)-3-[2-(2,6-Dimethyl-phenoxy)-ethanoylamino]-2-hydroxy-4-phenyl-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid cyclopropylmethyl-amide

White solid; IR (neat, cm⁻¹) 3413, 1648, 1531, 1443, 1390, 1196; ¹H NMR(DMSO-d₆) δ 8.12 (d, J=9.0, 1H), 8.06 (t, J=5.7, 1H), 7.33-7.13 (m, 5H),7.01-6.89 (m, 3H), 5.44 (d, J=6.8, 1H), 4.97 (d, J=9.0, 1H), 4.91 (d,J=9.0, 1H), 4.47-4.36 (m, 2H), 4.41 (s, 1H), 4.16 (d, J=14.2, 1H), 3.98(d, J=14.2, 1H), 3.10-2.76 (m, 4H), 2.13 (s, 6H), 1.51 (s, 3H), 1.38 (s,3H), 0.88 (m, 1H), 0.36 (m, 2H), 0.15 (m, 2H); HRMS (ESI) m/z calcd forC₃₀H₃₉N₃O₅SNa (M+Na)⁺ 576.2503, found 576.2503.

EXAMPLE 28 2,3-Dihydro-1H-indole-4-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-4-(cyclopropylmethyl-carbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Off white solid; ¹H NMR (DMSO-d₆) δ 8.03-8.01 (m, 2H), 7.35-7.11 (m,5H), 6.91 (t, J=7.7, 1H), 6.69 (d, J=7.9, 1H), 6.52 (d, J=7.7, 1H), 5.58(s br, 1H), 5.39 (d, J=6.8, 1H), 5.06 (d, J=9.2, 1H), 4.99 (d, J=9.2,1H), 4.48-4.39 (m, 4H), 2.98-2.79 (m, 6H), 1.51 (s, 3H), 1.37 (s, 3H),0.87 (m, 1H), 0.35 (m, 2H), 0.14 (m, 2H); HRMS (ESI) m/z calcd forC₂₉H₃₆N₄O₄SNa (M+Na)⁺ 559.2349, found 559.2353.

EXAMPLE B29 2,3-Dihydro-1H-indole-4-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-4-((S)-chroman-4-ylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Beige solid; ¹H NMR (DMSO-d₆) δ 8.52 (d, J=8.1, 1H), 8.21 (d, J=8.4,1H), 7.54-6.72 (m, 13H), 5.40 (d, J=5.9, 1H), 5.20-4.90 (m, 3H),4.70-4.12 (m, 3H), 3.10-2.80 (m, 4H), 2.20-1.90 (m, 6H), 1.51 (s, 3H),1.49 (s, 3H); HRMS (ESI) m/z calcd for C₃₄H₃₈N₄O₅SNa (M+Na)⁺ 685.2303,found 685.2319; Anal. Calcd for C₃₄H₃₈N₄O₅S.0.5H₂O: C, 65.47; H, 6.30;N, 8.98. Found: C, 65.34; H, 6.02; N, 8.75.

EXAMPLE B30(R)-3-{(2S,3S)-3-[2-(2,6-Dimethyl-phenoxy)-ethanoylamino]-2-hydroxy-4-phenyl-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-chroman-4-ylamide

White solid: mp=105-107° C.; ¹H NMR (DMSO-d₆) δ 8.49 (d, J=7.7, 1H),8.14 (d, J=8.6, 1H), 7.40-6.65 (m, 12H), 5.44 (d, J=7.3, 1H), 4.96 (d,J=8.6, 1H), 4.94 (d, J=8.6, 1H), 4.44-3.94 (m, 8H), 2.82-2.70 (m, 2H),2.15 (s, 6H), 2.10-1.90 (m, 2H), 1.49 (s, 3H), 1.45 (s, 3H); HRMS (ESI)m/z calcd for C₃₅H₄₁N₃O₆SNa (M+Na)⁺ 654.2608, found 654.2622; Anal.Calcd for C₃₅H₄₁N₃O₆S: C, 66.54; H, 6.54; N, 6.65. Found: C, 66.54; H,6.68; N, 6.69.

EXAMPLE B31(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[2-(1H-[1,2,4]triazol-3-ylsulfanyl)-ethanoylamino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-chroman-4-ylamide

¹H NMR (DMSO-d₆) δ 8.47 (d, J=8.2, 1H), 8.37 (d, J=8.6, 1H), 8.23 (s br,1H), 7.20-7.08 (m, 7H), 6.85-6.74 (m, 2H), 5.26 (d, J=6.6, 1H),4.98-4.89 (m, 3H), 4.41 (s, 1H), 4.30-4.20 (m, 4H), 3.75 (dd, J=22.2,14.5, 2H), 2.75-2.50 (m, 2H), 2.20-1.90 (m, 2H), 1.48 (s, 3H), 1.44 (s,3H); HRMS (ESI) m/z calcd for C₂₉H₃₄N₆O₅S₂Na (M+Na)⁺ 633.1924, found633.1930.

EXAMPLE B32((1S,2S)-1-Benzyl-3-{(R)-5,5-dimethyl-4-[(S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-thiazolidin-3-yl}-2-hydroxy-3-oxo-propyl)-carbamicacid 2,6-dimethyl-benzyl ester

White solid: mp=88-90° C.; ¹H NMR (DMSO-d₆) δ 8.30 (d, J=8.9, 1H), 8.15(d, J=9.3, 1H), 7.35-6.85 (m, 12H), 5.45 (d, J=6.0, 1H), 5.20-4.90 (m,2H), 4.45-3.90 (m, 6H), 2.80-2.62 (m, 2H), 2.14 (s, 6H), 1.90-1.60 (m,6H), 1.49 (s, 3H), 1.45 (s, 3H); HRMS (ESI) m/z calcd for C₃₆H₄₃N₃O₅SNa(M+Na)⁺ 652.2816, found 652.2836; Anal. Calcd for C₃₆H₄₃N₃O₅S: C, 68.65;H, 6.88; N, 6.67. Found: C, 68.45; H, 6.98; N, 6.58.

EXAMPLE B33((1S,2S)-1-Benzyl-3-{(R)-5,5-dimethyl-4-[(S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-thiazolidin-3-yl}-2-hydroxy-3-oxo-propyl)-carbamicacid (S)-(tetrahydro-furan-3-yl)ester

White solid: mp=103-105° C.; ¹H NMR (DMSO-d₆) δ 8.26 (d, J=7.9, 1H),7.30-7.08 (m, 10H), 5.50 (d, J=7.9, 1H), 5.00-4.90 (m, 3H), 4.42-4.38(m, 3H), 4.00-3.30 (m, 5H), 3.00-2.40 (m, 4H), 1.90-1.60 (m, 4H), 1.47(s, 3H), 1.43 (s, 3H), 1.40-1.38 (m, 2H); HRMS (ESI) m/z calcd forC₃₁H₃₉N₃O₆SNa (M+Na)⁺ 604.2452, found 604.2430; Anal. Calcd forC₃₁H₃₉N₃O₆S.0.25H₂O: C, 63.51; H, 6.79; N, 7.17. Found: C, 63.40; H,6.73; N, 7.08.

EXAMPLE B34 2,3-Dihydro-1H-indole-4-carboxylic acid[(1S,2S)-1-benzyl-3-((R)-5,5-dimethyl-4-prop-2-ynylcarbamoyl-thiazolidin-3-yl)-2-hydroxy-3-oxo-propyl]-amide

Orange solid; ¹H NMR (DMSO-d₆) δ 8.41 (t, J=5.0, 1H), 8.01 (d, J=8.3,1H), 7.34-7.11 (m, 5H), 6.91 (t, J=7.7, 1H), 6.68 (d, J=7.5, 1H), 6.52(d, J=7.9, 1H), 5.58 (s br, 1H), 5.45 (d, J=6.8, 1H), 5.06 (d, J=9.3,1H), 4.99 (d, J=9.5, 1H), 4.48-4.37 (m, 4H), 3.84 (m, 2H), 3.09 (m, 1H),2.98-2.81 (m, 4H), 1.50 (s, 3H), 1.35 (s, 3H); HRMS (ESI) m/z calcd forC₂₈H₃₂N₄O₄SNa (M+Na)⁺ 543.2036, found 543.2039.

EXAMPLE B35 1-H-indazole-4-carboxylic acid[1-benzyl-3-(5,5-dimethyl-4-prop-2-ynylcarbamoyl-thiazolidin-3-yl)-2-hydroxy-3-oxo-propyl]-amide

¹H NMR (DMSO-d₆) δ 13.18 (s, 1H), 8.42 (m, 2H), 8.19 (s, 1H), 7.68-7.12(m, 8H), 5.54 (d, J=5.6, 1H), 5.10 (d, J=9.3, 1H), 5.08 (d, J=9.3, 1H),4.54 (m, 2H), 4.41 (s, 1H), 3.87 (m, 2H), 3.03 (t, J=2.5, 1H), 2.89 (m,2H), 1.53 (s, 3H), 1.38 (s, 3H); HRMS (ESI) m/z calcd for C27H₂₉N₅O₄SNa(M+Na)⁺ 542.1832, found 542.1855; Anal. Calcd for C₂₇H₂₉N₅O₄S.0.25H₂O:C, 61.87; H, 5.67; N, 13.36; S, 6.12. Found: C, 61.85; H, 5.64; N,13.19; S, 6.08.

EXAMPLE B36(R)-3-{(2S,3S)-3-[2-(2,6-Dimethyl-phenoxy)-ethanoylamino]-2-hydroxy-4-phenyl-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid prop-2-ynylamide

White solid; IR (neat, cm⁻¹) 3418, 1658, 1530, 1378, 1196; ¹H NMR(DMSO-d₆) δ 8.46 (t, J=5.1, 1H), 8.10 (d, J=9.0, 1H), 7.33-7.14 (m, 5H),7.01-6.89 (m, 3H), 5.49 (d, J=6.8, 1H), 4.97 (d, J=9.2, 1H), 4.92 (d,J=9.0, 1H), 4.48-4.35 (m, 2H), 4.40 (s, 1H), 4.15 (d, J=14.3, 1H), 3.99(d, J=14.1, 1H), 3.93-3.86 (m, 2H), 3.10 (s, 1H), 2.77 (m, 2H), 1.50 (s,3H), 1.37 (s, 3H), 2.13 (s, 6H); HRMS (ESI) m/z calcd for C₂₉H₃₅N₃O₅SNa(M+Na)⁺ 560.2190, found 560.2168.

EXAMPLE B37 1-H-indazole-4-carboxylic acid(1-benzyl-3-{4[(furan-2-ylmethyl)-carbamoyl]-5,5-dimethyl-thiazolidin-3-yl}-2-hydroxy-3-oxo-propyl)-amide

¹H NMR (DMSO-d₆) δ 13.18 (s, 1H), 8.44 (m, 2H), 8.19 (s, 1H), 7.68-7.12(m, 9H), 6.34 (m, 1H), 6.26 (m, 1H), 5.54 (d, J=6.6, 1H), 5.10 (d,J=9.2, 1H), 5.06 (d, J=9.2, 1H), 4.55 (m, 2H), 4.44 (s, 1H), 4.29 (m,2H), 2.90 (m, 2H), 1.51 (s, 3H), 1.30 (s, 3H); HRMS (ESI) m/z calcd forC₂₉H₃₁N₅O₅SNa (M+Na)⁺ 584.1938, found 584.1922; Anal. Calcd forC₂₉H₃₁N₅O₅S.0.5H₂O: C, 61.03; H, 5.65; N, 12.27; S, 5.62. Found: C,61.14; H, 5.60; N, 12.17; S, 5.60.

EXAMPLE B38(R)-3-{(2S,3S)-3-[2-(2,6-Dimethyl-phenoxy)-ethanoylamino]-2-hydroxy-4-phenyl-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid (furan-2-ylmethyl)-amide

White solid; IR (neat, cm⁻¹) 3409, 1657, 1530, 1452, 1371, 1195; ¹H NMR(DMSO-d₆) δ 8.47 (t, J=5.7, 1H), 8.12 (d, J=8.8, 1H), 7.52 (s, 1H),7.32-7.14 (m, 5H), 7.01-6.89 (m, 3H), 6.33 (m, 1H), 6.26 (m, 1H), 5.50(d, J=7.0, 1H), 4.97 (d, J=9.0, 1H), 4.92 (d, J=9.0, 1H), 4.46-4.27 (m,5H), 4.15 (d, J=14.3, 1H), 4.00 (d, J=14.3, 1H), 2.79 (m, 2H), 2.14 (s,6H), 1.48 (s, 3H), 1.31 (s, 3H); HRMS (ESI) m/z calcd for C₃₁H₃₇N₃O₆SNa(M+Na)⁺ 602.2295, found 602.2310.

EXAMPLE B39 2,3-Dihydro-1H-indole-4-carboxylic acid((1S,2S)-1-benzyl-3-{(R)-4-[(furan-2-ylmethyl)-carbamoyl]-5,5-dimethyl-thiazolidin-3-yl}-2-hydroxy-3-oxo-propyl)-amide

Pale pink solid; ¹H NMR (DMSO-d₆) δ 8.42 (t, J=5.3, 1H), 8.02 (d, J=8.2,1H), 7.53 (s, 1H), 7.34-7.11 (m, 6H), 6.91 (t, J=7.7, 1H), 6.69 (d,J=7.7, 1H), 6.52 (d, J=7.7, 1H), 6.34 (m, 1H), 6.25 (m, 1H), 5.58 (s br,1H), 5.46 (d, J=6.6, 1H), 5.06 (d, J=9.2, 1H), 4.99 (d, J=9.2, 1H),4.48-4.18 (m, 5H), 4.40 (s, 1H), 3.00-2.79 (m, 4H), 1.48 (s, 3H), 1.30(s, 3H).

EXAMPLE B40(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[((S)-1-tetrahydro-furan-2-yl-methanoyl)-amino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid (furan-2-ylmethyl)-amide

Off white solid; ¹H NMR (DMSO-d₆) δ 8.44 (t, J=5.3, 1H), 7.57 (d, J=9.0,1H), 7.53 (s, 1H), 7.23-7.15 (m, 5H), 6.34 (m, 1H), 6.26 (m, 1H), 5.45(d, J=6.8, 1H), 4.94 (s, 2H), 4.39 (s, 2H), 4.28 (m, 3H), 4.10 (m, 1H),3.79-3.64 (m, 2H), 2.79-2.64 (m, 2H), 1.98-1.87 (m, 2H), 1.65-1.33 (m,2H), 1.47 (s, 3H), 1.30 (s, 3H); HRMS (ESI) m/z calcd for C₂₆H₃₃N₃O₆SNa(M+Na)⁺ 538.1982, found 538.1997.

EXAMPLE B41 2,3-Dihydro-1H-indole-4-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-4-((S)-cyclohex-2-enylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

¹H NMR (DMSO-d₆) δ 8.01 (d, J=8.2, 1H), 7.94 (d, J=7.7, 1H), 7.36-7.06(m, 5H), 6.90 (t, J=7.6, 1H), 6.69 (d, J=7.6, 1H), 6.52 (d, J=7.6, 1H),5.80-5.68 (m, 1H), 5.35 (d, J=6.7, 1H), 5.07 (d, J=9.2, 1H), 4.98 (d,J=9.2, 1H), 4.49-4.32 (m, 3H), 4.32-4.20 (m, 1H), 3.00-2.71 (m, 6H),2.00-1.60 (m, 6H), 1.49 (s, 3H), 1.37 (s, 3H); HRMS (ESI) m/z calcd forC₃₁H₃₈N₄O₄SNa (M+Na)⁺ 585.2506, found 585.2500; Anal. Calcd forC₃₁H₃₈N₄O₄S.1H₂O: C, 64.11; H, 6.94; N, 9.65. Found: C, 64.38; H, 6.72;N, 9.54.

EXAMPLE B42 2,3-Dihydro-1H-indole-4-carboxylic acid{(1S,2S)-1-benzyl-2-hydroxy-3-[(R)-4-((S)-indan-1-ylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-3-oxo-propyl}-amide

¹H NMR (DMSO-d₆) δ 8.32 (d, J=8.1, 1H), 8.06 (d, J=8.6, 1H), 7.33-7.11(m, 9H), 6.91 (t, J=7.6, 1H), 6.71 (d, J=7.6, 1H), 6.53 (d, J=7.6, 1H),5.36-5.25 (m, 2H), 5.09 (d, J=9.2, 1H), 5.01 (d, J=9.2, 1H), 4.50 (d,J=3.6, 1H), 4.44 (s, 1H), 4.42-4.32 (m, 1H), 2.97-2.71 (m, 6H),2.39-2.34 (m, 2H), 1.87-1.80 (m, 2H), 1.50 (s, 3H), 1.44 (s, 3H); HRMS(ESI) m/z calcd for C₃₄H₃₈N₄O₄SNa (M+Na)⁺ 621.2506, found 621.2519;Anal. Calcd for C₃₄H₃₈N₄O₄S.0.25H₂O: C, 67.69; H, 6.43; N, 9.29. Found:C, 67.73; H, 6.26; N, 8.98.

EXAMPLE B43(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2,4-dimethyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-indan-1-ylamide

¹H NMR (DMSO-d₆) δ 8.33 (d, J=7.7, 1H), 8.24 (s, 1H), 8.14 (d, J=8.4,1H), 7.32-7.12 (m, 9H), 6.86 (d, J=7.7, 1H), 6.53 (d, J=7.7, 1H),5.38-5.26 (m, 2H), 5.14 (d, J=9.2, 1H), 5.03 (d, J=9.2, 1H), 4.60-4.30(m, 4H), 2.95-2.64 (m, 3H), 2.42-2.30 (m, 1H), 1.90-1.80 (m, 1H), 2.12(s, 3H), 1.85 (s, 3H), 1.49 (s, 3H), 1.44 (s, 3H); HRMS (ESI) m/z calcdfor C₃₄H₃₉N₃O₅SNa (M+Na)⁺ 624.2503, found 624.2509; Anal. Calcd forC₃₄H₃₉N₃O₅S: C, 67.86; H, 6.53; N, 6.98. Found: C, 67.77; H, 6.50; N,6.79.

EXAMPLE B44 2,3-Dihydro-1H-indole-4-carboxylic acid[(1S,2S)-1-benzyl-3-((R)-5,5-dimethyl-4-{[(R)-1-(tetrahydro-furan-2-yl)methyl]-carbamoyl}-thiazolidin-3-yl)-2-hydroxy-3-oxo-propyl]-amide

White solid; IR (neat, cm⁻¹) 3401, 2978, 2861, 1643, 1531, 1455, 1372,1279, 1073; ¹H NMR (DMSO-d₆) δ 8.04 (m, 2H), 7.35-7.11 (m, .6H), 6.90(t, J=7.7, 1H), 6.68 (d, J=7.7, 1H), 6.52 (d, J=7.7, 1H), 5.58 (s br,1H), 5.39 (d, J=6.8, 1H), 5.06 (d, J=9.2, 1H), 4.97 (d, J=9.3, 1H),4.49-4.36 (m, 3H), 3.83-3.56 (m, 4H), 3.15 (m, 2H), 2.99-2.78 (m, 4H),1.78 (m, 4H), 1.50 (s, 3H), 1.36 (s, 3H); HRMS (ESI) m/z calcd forC₃₀H₃₈N₄O₅SNa (M+Na)⁺ 589.2455, found 589.2440.

EXAMPLE B45 2,3-Dihydro-1H-indole-4-carboxylic acid[(1S,2S)-1-benzyl-3-((R)-5,5-dimethyl-4-propylcarbamoyl-thiazolidin-3-yl)-2-hydroxy-3-oxo-propyl]-amide

Pink solid; ¹H NMR (DMSO-d₆) δ 8.01 (d, J=8.2, 1H), 7.89 (t, J=5.3, 1H),7.35-7.10 (m, 5H), 6.90 (t, J=7.8, 1H), 6.68 (d, J=7.8, 1H), 6.52 (d,J=7.8, 1H), 5.57 (s, 1H), 5.39 (d, J=6.9, 1H), 5.05 (d, J=9.2, 1H), 4.98(d, J=9.2, 1H), 4.49-4.40 (m, 2H), 4,35 (s, 1H), 3.04-2.78 (m, 8H), 1.49(s, 3H), 1.34 (s, 3H), 1.43-1.30 (m, 2H), 0.82 (t, J=7.5, 3H); HRMS(ESI) m/z calcd for C₂₈H₃₆N₄O₄SNa (M+Na)⁺ 547.2349, found 547.2323;Anal. Calcd for C₂₈H₃₆N₄O₅₄S.0.25H₂O: C, 63.55; H, 6.95; N, 10.59.Found: C, 63.33; H, 6.60; N, 10.46.

EXAMPLE B463-{(2S,3S)-3-[3-(2-Chloro-benzyl)-ureido]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-chloro-benzylamide

1H-NMR (400 MHz, dmso-d⁶): 7.00-7:40 (m, 13H), 4.00-4.80 (m, 9H), 2.60(m, 2H), 1.50, 1.40 (s, 3H), 1.26, 1.22 (s, 3H); MS (APCI, m/z): 628,630; C₃₁H₃₄C₁₂N₄O₄S Calculated: C, 58.14, H, 5.44, N, 8.90, Observed: C,58.54, H, 5.41, N, 8.71.

EXAMPLE B47{(1S,2S)-1-Benzyl-3-[(R)-4-(2-chloro-benzylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid allyl ester

Isolated yield: 68%; 1H-NMR (400 MHz, dmso-d⁶): 7.00-7.40 (m, 9H), 6.60(m, 1H), 5.80 (m, 1H), 5.32 (m, 1H), 5.19 (m, 1H), 4.00-5.00 (m, 9H),2.75 (m, 2H), 1.56, 1.51 (s, 3H), 1.36, 1.33 (s, 3H);

MS (APCI, m/z): 548 (M+H); C₂₇H₃₂ClN₃O₅S.0.89H₂O Calculated: C, 57.69,H, 6.06, N, 7.22, Observed: C, 57.30, H, 5.70, N, 7.22.

EXAMPLE B48{1-Benzyl-3-[4-(2-chloro-benzylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid prop-2-ynyl ester

Isolated yield: 45%; 1-H NMR (400 MHz, dmso-d⁶): 6.88-7.62 (m, 9H),4.20-5.00 (m, 9H), 2.70-2.90 (m, 2H), 2.42 (t, J=2.5 Hz, 1H), 1.56, 1.50(s, 3H), 1.37, 1.32 (s, 3H); MS (APCI, m/z): 545 (M+H);C₂₇H₃₀ClN₃O₅S.0.65H₂O Calculated: C, 58.35, H, 5.68, N, 7.56, Observed:C, 57.96, H, 5.48, N, 7.37.

EXAMPLE B493-{(2S,3S)-3-[3-(2,6-Difluoro-benzyl)-ureido]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2,6-difluoro-benzylamidea)

Isolated yield: 42%; 1H-NMR (400 MHz, dmso-d⁶): 6.60-7.40 (m, I 1H),4.00-4.80 (m, 9H), 2.60 (m, 2H), 1.50, 1.37 (s, 3H), 1.30, 1.13 (s, 3H),MS (APCI, m/z): 633; C₃₁H₃₂F₄N₄O₄S Calculated: C, 58.85, H, 5.10, N,8.86, Observed: C, 58.54, H, 5.00, N, 8.71.

EXAMPLE B50{(1S,2S)-1-Benzyl-3-[(R)-4-(2,6-difluoro-benzylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid allyl ester

Isolated yield: 71%; 1H-NMR (400 MHz, dmso-d⁶): 6.60-7.40 (m, 8H), 5.80(m, 1H), 5.05-5.35 (m, 2H), 4.00-5.00 (m, 9H), 2.75 (m, 2H), 1.56, 1.52(s, 3H), 1.37, 1.35 (s, 3H); MS (APCI, m/z): 548 (M+H);C₂₇H₃₂ClN₃O₅S.0.13H₂O Calculated: C, 8.97, H, 5.73, N, 7.64, Observed:C, 58.58, H, 5.61, N, 7.53.

EXAMPLE B51{1-Benzyl-3-[4-(2,6-difluoro-benzylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid prop-2-ynyl

Isolated yield: 73%; 1H-NMR (400 MHz, dmso-d⁶): 6.60-7.40 (m, 8H),4.20-5.00 (m, 9H), 2.70-2.90 (m, 2H), 2.42 (m, 1H), 1.56, 1.50 (s, 3H),1.38, 1.34 (s, 3H); MS (APCI, m/z): 546 (M+H); C₂₇H₃₀ClN₃O₅S Calculated:C, 59.44, H, 5.36, N, 7.70, Observed: C, 59.33, H, 5.39, N, 7.56.

EXAMPLE B523-{(2S,3S)-2-Hydroxy-4-phenyl-3-[3-(2-trifluoromethyl-benzyl)-ureido]-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-trifluoromethyl-benzylamide

Isolated yield: 82%; 1H-NMR (400 MHz, dmso-d⁶): 7.00-7.57 (m, 13H),4.00-4.80 (m, 9H), 2.60 (m, 2H), 1.46, 1.40 (s, 3H), 1.25, 1.22 (s, 3H);MS (APCI, m/z): 697 (M+H); C₃₃H₃₄F₆N₄O₄S Calculated: C, 56.89, H, 4.92,N, 8.04. Observed: C, 56.33, H, 4.78, N, 7.94.

EXAMPLE B53{(1S,2S)-1-Benzyl-3-[5,5-dimethyl-4-(2-trifluoromethyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid allyl ester

Isolated yield: 80%; 1H-NMR (400 MHz, dmso-d⁶): 7.00-7.70 (m, 9H), 5.80(m, 1H), 5.20 (m, 2H), 4.00-5.00 (m, 9H), 2.75 (m, 2H), 1.56, 1.50 (s,3H), 1.40, 1.29 (s, 3H); MS (APCI, m/z): 580 (M+H);C₂₈H₃₂F₃N₃O₅S.0.56H₂O Calculated: C, 57.70, H, 5.60, N, 7.21, Observed:C, 57.31, H, 5.31, N, 6.83.

EXAMPLE B54{1-Benzyl-3-[5,5-dimethyl-4-(2-trifluoromethyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid prop-2-ynyl ester

Isolated yield: 61%; 1H-NMR (400 MHz, dmso-d⁶): 6.90-7.60 (m,9H),4.20-5.00 (m, 9H), 2.60-2.80 (m, 2H), 2.42 (m, 1H), 1.55, 1.48 (s, 3H),1.40, 1.28 (s, 3H); MS (APCI, m/z): 578 (M+H); C₂₈H₃₀F₃N₃O₅S Calculated:C, 58.17, H, 5.24, N, 7.27, Observed: C, 57.78, H, 5.25, N, 6.94.

EXAMPLE B553-{(2S,3S)-3-[3-(3-Fluoro-phenyl)-ureido]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 40%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 1H), 8.39 (t,1H), 7.36-7.10 (m, 1 H), 6.91 (d, 1H), 6.65 (t, 1H), 6.45 (d, 1H), 5.33(br s, 1H), 4.98 (s, 2H), 4.49 (s, 2H), 4.38 (dd, 1H), 4.22-4.12 (m,2H), 2.58 (d, 2H), 2.55 (m, 1H), 2.24 (s, 3H), 1.49 (s, 3H), 1.35 (s,3H); MS-APCI (m/z+): 315, 579 (M+H).

EXAMPLE B56N-[(1S,2S)-3-(4-Allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl)-1-benzyl-2-hydroxy-3-oxo-propyl]-nicotinamide

White solid: ¹H NMR (DMSO-d₆) δ 8.81 (d, J=8.6, 1), 8.77 (d, J=6.2, 1H),8.12 (m, 1H), 7.99 (m, 1H), 7.63 (m, 1H), 7.32-7.12 (m, 7H), 5.78 (m,1H), 5.18 (m , 2H), 4.56 (m, 3H), 4.40 (m, 4H), 2.87-2.67 (m, 2H), 1.49(s, 3H), 1.34 (s, 3H); Anal. (C₂₆H₃₂N₄O₄S.0.5H₂O.0.5TFA) calculated C,(57.65), H, (6.36), N, (10.19), found C, (57.73), H, (5.91), N, (10.15).HRMS (ESI) m/z calcd for 483.2075, found 497.2066.

EXAMPLE B573-[(2S,3S)-3-(5-Bromo-thiophene-2-sulfonylamino)-2-hydroxy-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 33%. MS-APCI (m/z+): 667 (M+H); HPLC: Rf (min) 20.98;Purity: 97%.

EXAMPLE B583-[(2S,3S)-3-(4-Cyano-benzenesulfonylamino)-2-hydroxy-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 25%. MS-APCI (m/z+): 607 (M+H); HPLC: Rf (min) 20.71;Purity: 96%.

EXAMPLE B593-[(2S,3S)-3-(3-Benzyl-ureido)-2-hydroxy-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 69%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.35 (t, 1H), 7.29 (d,1H), 7.25-7.6 (m, 13H), 6.31 (t, 1H), 6.18 (d, 1H), 5.11 (d, 1H), 5.01(d, 1H), 4.95 (d, 1H), 4.48-4.45 (s, 2H), 4.37 (dd, 1H), 4.19-4.03 (m,4H), 2.70 (d, 1H), 2.53-2.46 (m, partially obscured by DMSO, 1H), 2.24(s, 3H), 1.49 (s, 314), 1.33 (s, 3H); MS-APCI (m/z+): 575 (M+H); HPLC:Rf (min.) 20.66; Purity: 97%, C₃₂H₃₈N₄O₄S.0.4H₂O calculated: 66.05,6.72, 9.63; found: 66.18, 6.70, 9.61.

EXAMPLE B603-{(S)-2-Hydroxy-3-[3-(4-methoxy-benzyl)-ureido]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 41%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (t, 1H),7.30-7.05 (m, 1H), 7.00 (d, 1H), 6.79 (d, 1H), 6.23 (t, 1H), 6.12 (d,1H), 5.10 (d, 1H), 5.02 (d, 1H), 4.94 (d, 1H), 4.48-4.44 (m, 2H), 4.38(dd, 1H), 4.14 (dd, 1H), 4.08-3.96 (m, 4H), 3.69 (s, 3H), 2.68 (d, 1H),2.24 (s, 3H), 1.49 (s, 3H), 1.33 (s, 3H); MS-APCI (m/z+): 605 (M+H).

EXAMPLE B613-[(2S,3S)-3-(3-Benzyl-ureido)-2-hydroxy-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid benzylamide

Isolated yield: 53%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (t, 1H),7.29-7.16 (m, 13H), 7.06 (d, 2H), 6.31-6.25 (m, 2H), 6.17 (d, 1H), 5.14(d, 1H), 5.00 (d, 1H), 4.95 (d, 1H), 4.47-4.34 (m, 2H), 4.25-4.03 (m,4H), 2.72 (d, 1H), 1.48 (s, 3H), 1.31 (s, 3H); MS-APCI (m/z+): 561;C₃₁H₃₆N₄O₄S.0.3H₂O calculated: C, 65.77, H, 6.52, N, 9.90, found: C,65.70, H, 6.50, N 9.90.

EXAMPLE B623-{(2S,3S)-2-Hydroxy-3-[3-(2-methyl-benzyl)-ureido]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 84%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (t, 1H),7.30-7.04 (m, 12H), 6.97 (d, 1H), 6.21-6.15 (m, 2H), 5.11 (d, 1H), 5.02(d, 1H), 4.93 (d, 1H), 4.48-4.44 (m, 2H), 4.39 (dd, 1H), 4.19-4.04 (m,4H), 2.67 (d, 2H), 2.24 (s, 3H), 2.14 (s, 3H), 1.48 (s, 3H), 1.33 (s,3H); MS-APCI (m/z+): 589; HPLC: Rf (min) 21.25; Purity: 100%.

EXAMPLE B633-{(2S,3S)-2-Hydroxy-3-[3-(4-methoxy-benzyl)-ureido]-4-phenyl-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 4-methoxy-benzylamide

Isolated yield: 59%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (t, 1H),7.22-7.14 (m, 8H), 7.00 (d, 2H), 6.83-6.77 (m, 3H), 6.23-6.21 (m, 2H),6.11 (d, 1H), 5.11 (d, 1H), 5.00 (d, 1H), 4.94 (d, 1H), 4.46-4.41 (m,2H), 4.29-3.96 (m, 4H), 3.69 (s, 3H), 3.65 (s, 3H), 2.68 (d, 1H), 1.47(s, 3H), 1.28 (s, 3H); MS-APCI (m/z+): 121, 621; HPLC: Rf (min) 20.68;Purity: 98%.

EXAMPLE B64{(1S,2S)-1-Benzyl-2-hydroxy-3-[4-(4-methoxy-benzylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-3-oxo-propyl}-carbamicacid prop-2-ynyl ester

Isolated yield: 64%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (t, 1H), 7.46 (d,1H), 7.27-7.13 (m, 8H), 6.79 (d, 2H), 5.34 (d, 1H), 4.93 (dd, 2H), 4.50(s, 2H), 4.40 (s, 2H), 4.29 (dd, 1H), 4.14 (dd, 1H), 3.97-3.88 (m, 1H),3.67 (s, 3H), 2.72-2.58 (m, 2H), 1.48 (s, 3H), 1.27 (s, 3H); MS-APCI(m/z+): 540; HPLC: Rf (min) 19.07; Purity: 100%; C₁₈H₃₃N₃O₆S.0.4H₂O:calcd: C, 61.50, H, 6.23, N, 7.68; found: C, 61.54, H, 6.37, N, 7.63.

EXAMPLE B653-[(2S,3S)-2-Hydroxy-3-((S)-2-methyl-butyrylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 98%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (t, 1H), 7.92 (d,1H), 7.31-7.26 (m, 3H), 7.18-7.08 (m, 6H), 5.19 (d, 1H), 5.10 (d, 1H),4.92 (d, 1H), 4.48 (s, 1H), 4.40 (dd, 1H), 4.19-4.14 (m, 2H), 2.69-2.57(m, 2H), 2.26 (s, 3H), 2.13-2.08 (m, 1H), 1.48 (s, 3H), 1.44-1.36 (m,1H), 1.33 (s, 3H); 1.20-1.14 (m, H), 0.75-0.65 (m, 6H): MS-APCI (m/z+):265, 526 (M+H); C₂₉H₃₉N₃O₄S: calcd: C, 66.26, H, 7.48, N, 7.99, found:C, 65.93, H, 7.59, N, 7.83.

EXAMPLE B663-{(2S,3S)-2-Hydroxy-3-[3-(2-methyl-benzyl)-ureido]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid (pyridin-4-ylmethyl)-amide

Isolated yield: 41%. MS-APCI (m/z+): 225, 576; HPLC: Rf (min) 17.93;Purity: 98%; C₃₁H₃₇N₅O₄S.0.6H₂O: calcd: C, 63.48, H, 6.56, N, 11.94;found: C, 63.41, H, 6.44, N, 11.87.

EXAMPLE B67((1S,2S)-1-Benzyl-3-{5,5-dimethyl-4-[(pyridin-4-ylmethyl)-carbamoyl]-thiazolidin-3-yl}-2-hydroxy-3-oxo-propyl)-carbamicacid prop-2-ynyl ester

Isolated yield: 22%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.55 (t, 1H), 8.49 (d,2H), 7.46 (d, 1H), 7.28 (d, 2H), 7.26-7.09 (m, 6H), 5.42 (d, 1H), 4.97(d, 1H), 4.47-4.38 (m, 5H), 4.93 (d, 1H), 4.23 (dd, 1H), 3.92-3.88 (m,1H), 2.72-2.56 (m, 2H), 1.51 (s, 3H), 1.33 (s, 3H); MS-APCI (m/z+): 455,511; HPLC: Rf (min) 16.76; Purity: 100%.

EXAMPLE B683-{(2S,3S)-2-Hydroxy-3-[(1-methyl-1H-pyrrole-3-carbonyl)-amino]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid (pyridin-4-ylmethyl)-amide

Isolated yield: 21%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (t, 1H), 8.41 (d,2H), 7.90 (d, 1H), 7.30 (d, 2H), 7.25 (d, 2H), 7.21-7.19 (m, 1H), 7,14(t, 1H), 7.07 (t, 1H), 6.81-6,78 (m, 2H), 5.95-5.92 (m, 1H), 5.45 (d,1H), 5.12 (d, 1H), 5.00 (d, 1H), 4.49-4.34 (m, 3H), 4.32-4.29 (m, 1H),4.22 (dd, 1H), 3.68 (s, 3H), 2.81-2.76 (m, 2H), 1.52 (s, 3H), 1.34 (s,3H); MS-APCI (m/z+): 536; HPLC: Rf (min) 17.58; Purity: 96%.

EXAMPLE B693-{3-[3-(2,4-Dimethyl-benzyl)-ureido]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 17%; MS-APCI (m/z+): 603; HPLC: Rf (min) 21.96; Purity:97%.

EXAMPLE B703-{2-Hydroxy-3-[3-(2-methoxy-benzyl)-ureido]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 18%; MS-APCI (m/z+): 605; HPLC: Rf (min) 21.72; Purity:94%.

EXAMPLE B713-{3-[3-(2,4-Difluoro-benzyl)-ureido]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 12%; MS-APCI (m/z+): 611; HPLC: Rf (min) 21.00; Purity:86%.

EXAMPLE B723-{3-[3-(2-Bromo-benzyl)-ureido]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 16%; MS-APCI (m/z+): 442, 468, 655; HPLC: Rf (min)21.59; Purity: 94%.

EXAMPLE B733-{3-[3-(4-Bromo-benzyl)-ureido]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 5%; MS-APCI: 652 (M−H); HPLC: Rf (min) 22.12; Purity:95%.

EXAMPLE B74(R)-3-{(2S,3S)-3-[3-(3,4-Dimethoxy-benzyl)-ureido]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 24%; MS-APCI (m/z+): 635; HPLC: Rf (min) 19.44; Purity:88%.

EXAMPLE B75(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[3-(3-trifluoromethyl-benzyl)-ureido]-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 19%; MS-APCI (m/z+): 643; HPLC: Rf (min) 21.87; Purity:95%.

EXAMPLE B76(R)-3-{(2S,3S)-2-Hydroxy-3-[3-(3-methoxy-benzyl)-ureido]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 35% MS-APCI (m/z+): 605; HPLC: Rf (min) 20.63; Purity:95%.

EXAMPLE B77(R)-3-{(2S,3S)-3-[2-(2,6-Dichloro-phenoxy)-acetylamino]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 75%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (t, 1H), 8.12 (d,1H), 7.47 (d, 2H), 7.30-7.22 (m, 3H), 7.20-7.06 (m, 7H), 5.49 (d, 1H),4.96 (d, 1H), 4.94 (d, 1H), 4.48-4.45 (m, 2H), 4.40-4.33 (m, 3H),4.23-4.14 (m, 2H), 2.78-2.69 (m, 2H), 2.24 (s, 3H), 1.49 (s, 3H), 1.334(s, 3H); MS-APCI (m/z+): 644, 646. HPLC: Rf (min) 22.23; Purity: 98%.

EXAMPLE B78(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[(1-o-tolyl-methanoyl)-amino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-indan-1-ylamide

IR (neat, cm⁻¹) 3311, 3026, 2966, 1655, 1538, 1454, 1222, ¹H NMR (DMSO)δ 8.40-8.25 (m, 2H), 7.40-7.10 (m, 13H), 5.43 (d, J=6.9, 1H), 5.30 (dd,J=15.0, 7.6, 1H), 5.14 (d, J=9.3, 1H), 5.04 (d, J=9.3, 1H), 4.54-4.30(m, 3H), 3.00-2.60 (m, 4H), 2.42-2.30 (m, 1H), 2.02 (s, 3H), 1.90-1.80(m, 1H), 1.49 (s, 3H), 1.44 (s, 3H) HRMS (ESI) m/z calcd for C₃₃H₃₈N₃O₄S(M+H)⁺ 572.2581, found 572.2583.

EXAMPLE B79(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[(1-o-tolyl-methanoyl)-amino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid (thiophen-2-ylmethyl)-amide

IR (neat, cm⁻¹) 3306, 3062, 2966, 1651, 1538, 1454, 1369, 1222, 1110,700, ¹H NMR (DMSO) δ 8.54 (t, J=6.0, 1H), 8.21 (d, J=7.9, 1H), 7.40-7.10(m, 1H), 6.90 (dd, J=5.0, 3.5, 1H), 5.51 (d, J=6.6, 1H), 5.10 (d, J=9.3,1H), 5.01 (d, J=9.3, 1H), 4.60-4.30 (m, 5H), 2.92-2.62 (m, 2H), 2.04 (s,3H), 1.48 (s, 3H), 1.32 (s, 3H) HRMS (ESI) m/z calcd for C₂₉H₃₄N₃O₄S₂(M+H)⁺ 552.1989, found 552.1991.

EXAMPLE B80(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[(1-o-tolyl-methanoyl)-amino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-cyclohex-2-enylamide

IR (neat, cm⁻¹) 3316, 2932, 1632, 1530, 1452, 1242, 1109, ¹H NMR (DMSO)δ 8.25 (d, J=8.2, 1H), 7.95 (d, J=7.9, 1H), 7.40-7.05 (m, 9H), 5.80-5.70(m, 2H), 5.50-5.40 (m, 1H), 5.39 (d, J=6.9, 1H), 5.12 (d, J=9.2, 1H),5.00 (d, J=9.2, 1H), 4.54-4.20 (m, 3H), 2.90-2.62 (m, 2H), 2.02 (s, 3H),2.00-1.60 (m, 6H), 1.48 (s, 3H), 1.37 (s, 3H); HRMS (ESI) m/z calcd forC₃₀H₃₈N₃O₄S (M+H)⁺ 536.2568, found 536.2583.

EXAMPLE B81(R)-3-((2S,3S)-3-{[1-(3-Fluoro-2-methyl-phenyl)-methanoyl]-amino}-2-hydroxy-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-cyclohex-2-enylamide

White solid: ¹H NMR (DMSO) δ 8.37 (d, J=8.8, 1H), 7.95 (d, J=7.7, 1H),7.40-6.90 (m, 8H), 5.80-5.70 (m, 2H), 5.50-5.40 (m, 2H), 5.10 (d, J=8.9,1H), 5.00 (d, J=8.9, 1H), 4.60-4.20 (m, 3H), 2.90-2.60 (m, 2H),2.00-1.89 (m, 2H), 1.88 (s, 3H), 1.80-1.60 (m, 4H), 1.48 (s, 3H), 1.37(s, 3H); HRMS (ESI) m/z calcd for C₃₀H₃₇N₃O₄SF (M+H)⁺ 554.2502, found554.2489.

EXAMPLE B82(R)-3-((2S,3S)-3-{[1-(3-Fluoro-2-methyl-phenyl)-methanoyl]-amino}-2-hydroxy-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (S)-indan-1-ylamide

White solid: ¹H NMR (DMSO) δ 8.43 (d, J=8.8, 1H), 8.34 (d, J=7.9, 1H),7.40-7.10 (m, 11H), 6.95 (d, J=7.2, 1H), 5.47 (d, J=6.8, 1H), 5.30 (dd,J=15.6, 7.9, 1H), 5.13 (d, J=9.2, 1H), 5.04 (d, J=9.2, 1H), 4.50-4.30(m, 3H), 3.00-2.60 (m, 4H), 2.42-2.30 (m, 1H), 1.89 (s, 3H), 1.90-1.79(m, 1H), 1.49 (s, 3H), 1.41 (s, 3H); HRMS (ESI) m/z calcd forC₃₃H₃₇N₃O₄FS (M+H)⁺ 590.2489, found 590.2486.

EXAMPLE B83(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-1-thia-3-aza-spiro[4.4]nonane-4-carboxylicacid (S)-indan-1-ylamide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.33 (d, 1H, J=8.1), 8.20 (d, 1H,J=8.4), 7.30-7.13 (m, 9H), 6.94 (t, 1H, J=8.24), 6.76 (d, 1H, J=7.9),6.54 (d, 1H, J=7.9), 5.40 (d, 1H, J=6.4), 5.29 (m, 1H), 5.13 (d, 1H,J=9.3), 4.98 (d, 1H, J=9.3), 4.60 (s, 1H), 4.51 (m, 1H), 4.40 (m, 1H),2.96-2.63 (m, 4H), 2.54-2.26 (m, 2H), 2.04-1.68 (m, 8H), 1.79 (s, 3H).Exact mass calculated for C₃₅H₄₀N₃O₅S (M+H)⁺ 614.2689, found 614.2678.

EXAMPLE B84(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-1-thia-3-aza-spiro[4.5]decane-4-carboxylicacid (S)-cyclohex-2-enylamide

¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.14 (d, 1H, J=8.6), 8.01 (d, 1H,J=7.9), 7.34-7.13 (m, 5H), 6.90 (t, 1H, J=7.9), 6.78 (d, 1H, J=5.3),6.52 (d, 1H, J=7.3), 5.57-5.72 (m, 1H), 5.48-5.44 (m, 1H), 5.36 (d, 1H,J=7.0), 5.05 (d, 1H, J=9.0), 4.91 (d, 1H, J=9.0), 4.55 (s, 1H),4.49-4.46 (m, 1H), 4.42-4.28 (m, 2H), 2.79-2.69 (m, 2H), 1.93 (m, 2H),1.79 (s, 3H), 1.77-1.45 (m, 14H). Exact mass calculated for C₃₃H₄ ₂N₃O₅S(M+H)⁺ 592.2845, found 592.2842.

EXAMPLE B85(R)-3-[(2S,3S)-2-Hydroxy-3-(4-hydroxy-butyrylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

¹H NMR (DMSO-d₆) δ 8.36 (t, 1H, J=5.9), 7.97 (d, 1H, J=8.2), 7.31-7.09(m, 9H), 5.23 (d, 1H, J=7.2), 5.05 (d, 1H, J=9.2), 4.92 (d, 1H, J=9.2),4.48 (s, 1H), 4.44-4.34 (m, 2H), 4.19-4.13 (m, 2H), 3.26-3.20 (m, 2H),2.72-2.54 (m, 2H), 2.25 (s, 3H), 2.04-1.98 (m, 2H), 1.49 (s, 3H),1.47-1.38 (m, 2H), 1.34 (s, 3H). (no peak for primary OH) Exact masscalculated for C₂₈H₃₈N₃O₅S (M+H)⁺ 528.2532, found 528.2540. Anal. Calcdfor C₂₈H₃₇N₃O₅S.0.3H₂O: C, 63.08; H, 7.11; N, 7.88. Found: C, 62.95; H,6.88; N, 7.56.

The synthesis of compounds with the general structure 24 is as follows.The boc-protected carboxylic acids 20a-j are coupled to the requisiteamines 2 to yield amino amides 23 using a two step process. The processincludes treatment of 20 with 2 in the presence of either diphenylchlorophosphate or EDCI, followed by exposure to HCl or methane sulfonicacid. Final compounds 24 are obtained by a DCC-mediated coupling of 23and 4 followed by deprotection of the P2 phenol. Final compounds werepurified either by flash chromatography or preparative HPLC.

The synthesis of compounds of the general structure 31 (where P2 is not2-methyl -3-hydroxy benzamide) is as follows. Amino amides of thegeneral structure 23 were coupled to the Boc-acid intermediate 15 usingDCC coupling conditions. The resulting intermediate 29 was deprotectedunder acidic conditions to yield amine of the general structure 30.Final compounds were obtained by modification of amine 30 by methodsdescribed in General Methods B section to give P2 amides, ureas, andcarbamates.

Methods Used for Synthesis of Compounds with P1 Variations.

EDCI coupling—To a solution of acid, amine and HOBT in CH₂Cl₂ was addedEDCI and the solution stirred overnight at room temperature. Thesolution was concentrated in vacuo and the residue dissolved in ethylacetate and a small portion of water. The solution was washed withsaturated NH₄Cl (2×), saturated NaHCO₃ (2×), brine (1×), dried withMgSO₄ and concentrated in vacuo. The crude used without furtherpurification unless otherwise noted.

DCC coupling—A solution of acid, amine and HOBT was prepared in ethylacetate. To the solution was then added DCC in an EtOAc solution at 0°C. and the mixture was stirred overnight at room temperature. Themixture was filtered and the filtrate was concentrated in vacuo. Theresidue dissolved in ethyl acetate washed with saturated NH₄Cl (1×),saturated NaHCO₃ (1×), brine (1×), dried over Na₂SO₄ and concentrated invacuo. The crude was used without further purification unless otherwisenoted.

4N HCl Boc deprotection—To a solution of Boc-amine in dioxane was added4N HCl solution in dioxane and the solution stirred overnight at roomtemperature. The solution was poured into saturated NaHCO₃ and theproduct was extracted into ethyl acetate. The organic solution waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Thecrude was used without further purification unless otherwise noted.

MeSO₃H Boc deprotection—To a solution of Boc-amine in ethyl acetate at0° C. was added methane sulfonic acid and the solution stirred 3-6 h atroom temperature. The solution was cooled to 0° C. and sufficientsaturated NaHCO₃ was added to quench the acid. The solution was dilutedwith ethyl acetate, washed with saturated NaHCO₃ and brine, dried overNa₂SO₄ and concentrated in vacuo. The crude used without furtherpurification unless otherwise noted.

KCN Phenolic acetate deprotection—A solution of phenolic acetate and KCNin ethanol was heated at 50° C. overnight. The solution was concentratedin vacuo. The residue was purified by flash chromatography eluted with 0to 5% methanol in CH₂Cl₂ unless otherwise noted.

NaOMe/MeOH Phenolic acetate deprotection—0.5 N NaOCH₃/MeOH Phenolicacetate deprotection—A solution of phenolic acetate in EtOAc andmethanol was cooled to 0° C. in an ice bath. 0.5 N NaOCH₃/MeOH was thenadded dropwise and then stirred at 0° C. for 1.5-2 hrs followingaddition. Additional EtOAc was then added, the 0.15 N HCl (4.5 eq.)added dropwise. The phases were separated and organic phase washed with2.5% Na₂CO₃ aqueous solution, then with 0.1 N HCl/brine (2:1), followedwith brine, dried with MgSO₄ and concentrated in vacuo. The resultingresidue subjected to flash silica gel chromatography to afford thedesired product unless otherwise noted.

HCl/MeOH Phenolic acetate deprotection—To a solution of phenolic acetatein methanol was added 4N HCl in dioxane and the solution stirred at roomtemperature ca. 4 h. The solution was concentrated in vacuo. The residuewas purified by flash chromatography eluted with 0 to 5% methanol inCH₂Cl₂ unless otherwise noted.

Source of Boc-carboxylic Acids 20a-j

Boc-acids 20a, 20b and 20c were prepared following the procedure ofDemange, L; Ménez, A; Dugave, C. Tet. Lett. 1998, 39, 1169.

Boc-acid 20d was prepared in the following way.

(2S)-3,3-Dimethyl-4-oxo-N-(9-phenylfluorenyl)proline methyl ester (F2):

The known ketone F1 (Blanco, M.-J; Sardina, F. J. J. Org. Chem. 1996,61, 4748) (14.2 g, 37 mmol) was dimethylated following the procedure ofSharma and Lubell (Sharma, R; Lubell, W. D. J. Org. Chem. 1996, 61, 202)for the benzyl ester analog. The crude was purified by flashchromatography eluted with 0 to 10% ethyl acetate in hexanes. Isolatedyield: 7.86 g (52%). ¹H NMR (400 MHz, CDCl₃): δ 7.74 (d, 1H), 7.67 (d,1H), 7.43-7.23 (m, 11H), 3.97 (d, 1H), 3.75 (d, 1H), 3.43 (s, 1H), 2.95(s, 3H), 1.38 (s, 3H), 0.84 (s, 3H); MS-APCI (m/z+): 412, 241.

(2S)-3,3-Dimethyl-4-oxo-N-(Boc)proline methyl ester (F3):

To a solution of 9-phenylfluorene-protected amine F2 (300 mg, 0.73 mmol)and di-tert-butyl dicarbonate (320 mg, 1.5 mmol) in tetrahydrofuran (50mL) was added 20 wt % palladium on carbon (100 mg), and the slurry wastreated with 50 psi hydrogen gas for 40 h. The solution was filtered andconcentrated in vacuo. The crude was purified by chromatography elutedwith hexane, 10% ethyl acetate/hexane, and 25% ethyl acetate/hexane.Isolated yield: 182 mg (92%). ¹H NMR (400 MHz, CDCl₃): δ 4.42 (s)+4.31(s) (1H), 4.05 (d)+4.01 (d) (1H), 3.96 (d)+3.94 (d) (1H), 3.72 (s, 3H),1.48 (s)+1.45 (s) (9H), 1.29 (s)+1.27 (s) (3H), 1.07 (s)+1.06 (s) (3H);MS-APCI (m/z+): 172.

(2S)-4,4-Difluoro-3,3-dimethyl-N-(Boc)proline methyl ester (F4):

A solution of ketone F3 (1.1 g, 4.1 mmol) and diethylaminosulfurtrifluoride (4.3 mL, 32 mmol) in anhydrous dichloroethane (40 mL) washeated at 70° C. for 11 h. The solution was then cooled to ambienttemperature and poured slowly into ice-cooled satd. NaHCO₃ soln (75 mL).The solution was diluted with ethyl acetate (100 mL) and washed with theNaHCO₃ soln, water (1×100 mL) and brine (1×100 mL), dried with magnesiumsulfate and concentrated in vacuo. The crude was purified by flashchromatography eluted with 0 to 10% ethyl acetate in hexanes. Isolatedyield: 0.75 g (63%). ¹H NMR (400 MHz, DMSO-d₆): δ 4.15 (s)+4.07 (s)(1H), 3.88-3.77 (m, 2H), 3.76 (s)+3.75 (s) (3H), 1.47 (s)+1.41 (s) (9H),1.27 (s, 3H), 1.06 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−112.8 (dt,J=230, 13 Hz)+−114.2 (dt, J=230, 15 Hz) (IF), −114.2 (dt, J=230, 14Hz)+−115.1 (dt, J=230, 11 Hz) (1F); MS-APCI (m/z+): 194.

(2S)-4,4-Difluoro-3,3-dimethyl-N-(Boc)proline (20d):

To a solution of methyl ester F4 (4.7 g, 16 mmol) in methanol (100 mL)was added a solution of LiOH (6.8 g, 160 mmol) in water (50 mL) and thesolution was heated at 50° C. for 14 h. The methanol was removed invacuo and the remaining solution was diluted with water (200 mL). Theaqueous solution was extracted with ether (2×200 mL), acidified with 1NHCl (200 mL) and extracted again with ether (2×200 mL). The combinedorganics were washed with brine (1×200 mL), dried with magnesium sulfateand concentrated in vacuo. The while solid was dried overnight at 40° C.under vacuum. Isolated yield: 4.3 g (95%). ¹H NMR (400 MHz, DMSO-d₆): δ12.95 (bs, 1H), 3.93 (s, 1H), 3.84-3.74 (m, 2H), 1.38 (s)+1.33 (s) (9H),1.19 (s, 3H), 1.01 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−111.4 (dt,J=227, 13 Hz)+−112.4 (dt, J=227, 13 Hz) (1F), −113.5 (dt, J=227, 14Hz)+−113.9 (dt, J=227, 15 Hz) (1F); MS-APCI (m/z+): 180.1 (m/z−): 278.

Boc-acids 20e, 20f, 20g and 20h were prepared following the procedure ofKaranewsky, D; et al. J. Med. Chem. 1990, 33, 1459.

Boc-acids of the general structure 20i were prepared by the followingmethod.

Example for n=2:

The known amino thiol (n=2) (Nagasawa, H. T; et al. J. Med. Chem. 1987,30, 1373.) (0.78 g, 3.7 mmol) was stirred in H₂O (10 mL) at room temp.The mixture was treated with 37% aqueous formaldehyde (0.36 mL, 4.8mmol) and the result was stirred overnight at room temp. Next, Bocanhydride (0.96 g, 4.4 mmol) was added as a soln. in THF (5 mL). Theresult was stirred overnight at room temp. The desired product wasisolated and purified by acid-base extraction. (2N HCl, sat. bicarb, andEtOAc).

The result 20i (n=2) was a white solid. Yield: (92%). ¹H NMR (CDCl₃): δ4.82-4.35 (m, 3H), 2.21-1.79 (m, 8H), 1.54 (s, 9H).

Boc-acid 20j was prepared following the procedure of Hursthouse, M. B.,et al. J. Chem. Soc. Perkin Trans. 1, 1995, 2419-2425.

Boc-acid 20k was obtained by mild base hydrolysis of intermediate F3from the preparation of Boc-acid 20d.

Specific Method C

EXAMPLE C1(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid 2-methyl-benzylamide

The title compound was prepared according to general methods usingcarboxylic acid 20a (0.96 g, 3.8 mmol), o-methylbenzyl amine (0.57 mL,4.6 mmol), HOBT (0.62 g, 4.6 mmol), EDCI (0.88 g, 4.6 mmol), CH₂Cl₂ (50mL). To give the crude Boc-amide (MS-APCI (m/z+): 355, 255) (1.35 g, 3.8mmol). The Boc was removed using the general 4N HCl Boc deprotection. 4NHCl in 1,4-dioxane (5 mL), 1,4-dioxane (5 mL). The result was aminoamide of general structure 23. Isolated yield: 0.79 g (71%, 2 steps). ¹HNMR (400 MHz, DMSO-d₆): δ 9.02 (t, 1H), 7.24-7.14 (m, 4H), 4.55 (t, 1H),4.35 (dd, 1H), 4.30 (dd, 1H), 3.73 (m, 2H), 2.94 (m, 2H), 2.52 (m, 1H),2.27 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−95.3 (dq, J=235, 15 Hz, 1F),−96.5 (dq, J=235, 12 Hz, 1F); MS-APCI (m/z+): 255.

Amino amide 23 (100 mg, 0.34 mmol) was coupled to carboxylic acid 4 (140mg, 0.38 mmol) using the general DCC coupling method outlined above.HOBT (51 mg, 0.38 mmol), DCC (78 mg, 0.38 mmol), TEA (50 μL, 0.36 mmol),CH₂Cl₂ (10 mL). The crude was purified by chromatography eluted with 10%acetone in CH₂Cl₂. Isolated yield: 0.13 g (63%). MS-APCI (m/z+): 608.This material was subjected to the general KCN phenolic acetatedeprotection conditions (130 mg, 0.21 mmol), KCN (1 mg, 15 μmol),ethanol (10 mL). The crude was precipitated from diethyl ether and ethylacetate with hexanes at −78° C. Isolated yield: 0.10 g (84%). ¹H NMR(400 MHz, DMSO-d₆): δ 9.37 (s, 1H), 8.36 (t, 1H), 8.16 (d, 1H),7.32-7.09 (m, 9H), 6.93 (t, 1H), 6.76 (d, 1H), 6.54 (d, 1H), 5.49 (d,1H), 4.66 (dd, 1H), 4.34-4.15 (m, 6H), 2.85-2.67 (m, 3H), 2.40 (m, 1H),2.22 (s, 3H), 1.79 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−98.7 (m, 2F);MS-APCI (m/z+): 566; HPLC Purity: 100%; Rf (min.) 19.01; Anal.C₃₁H₃₃N₃O₅F₂.0.3H₂O C, H, N calcd: C, 65.21, H, 5.93, N, 7.36; found: C,65.1 1, H, 5.90, N, 7.17.

EXAMPLE C2(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-pyrrolidine-2-carboxylicacid (S)-indan-1-ylamide

White solid; IR (neat, cm⁻¹) 3308, 3070, 2962, 1651, 1585, 1538, 1372,1259, 1098; ¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.36 (d, J=8.2, 1H), 8.21(d, J=7.9, 1H), 7.33-7.14 (m, 9H), 6.96-6.91 (m, 1H), 6.77 (d, J=8.2,1H), 6.55 (d, J=1.7, 1H), 5.41 (d, J=6.6, 1H), 5.28 (dd, J=15.0, 7.9,1H), 4.68 (d, J=5.5, 1H), 4.63 (d, J=5.5, 1H), 4.40-4.20 (m, 3H),3.00-2.62 (m, 4H), 2.50-2.30 (m, 4H), 1.79 (s, 3H); HRMS (ESI) m/z calcdfor C₃₂H₃₄N₃O₅F₂ (M+H)⁺ 578.2467, found 578.2476; Anal. Calcd forC₃₂H₃₃N₃O₅F₂: C, 66.54; H, 5.76; N, 7.27. Found: C, 66.35; H, 5.70; N,7.20.

EXAMPLE C3(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-pyrrolidine-2-carboxylicacid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide

IR (neat, cm⁻¹) 3300, 2934, 1651, 1520, 1455, 1368, 1284; ¹H NMR(DMSO-d₆) δ 9.35 (s, 1H), 8.35 (d, J=8.2, 1H), 8.21 (d, J=8.2, 1H),7.34-7.10 (m, 9H), 6.96-6.91 (m, 1H), 6.77 (d, J=8.1, 1H), 6.55 (d,J=7.5, 1H), 5.40 (d, J=6.4, 1H), 5.00-4.90 (m, 1H), 4.65 (d, J=6.2, 1H),4.63 (d, J=6.2, 1H), 4.40-4.20 (m, 3H), 3.00-2.60 (m, 4H), 2.50-2.40 (m,2H), 1.90-1.60 (m, 4H), 1.79 (s, 3H); HRMS (ESI) m/z calcd forC₃₃H₃₆N₃O₅F₂ (M+H)⁺ 592.2623, found 592.2610; Anal. Calcd forC₃₃H₃₅N₃O₅F₂.1H₂O: C, 65.01; H, 6.12; N, 6.89. Found: C, 65.07; H, 5.99;N, 6.75.

EXAMPLE C4(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-pyrrolidine-2-carboxylicacid (S)-cyclohex-2-enylamide

White solid; IR (neat, cm⁻¹) 3002, 2944, 1650, 1535, 1456, 1371, 1282,1100; ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.18 (d, J=8.2, 1H), 8.01 (d,J=8.2, 1H), 7.35-7.13 (m, 5H), 6.96-6.91 (m, 1H), 6.76 (d, J=8.1, 1H),6.54 (d, J=7.5, 1H), 5.77-5.73 (m, 1H), 5.49-5.45 (m, 1H), 5.39 (d,J=6.7, 1H), 4.60 (d, J=5.9, 1H), 4.56 (d, J=5.9, 1H), 4.40-4.10 (m, 4H),2.90-2.60 (m, 4H), 2.50-2.30 (m, 2H), 1.79 (s, 3H), 1.78-1.60 (m, 2H),1.60-1.38 (m, 2H); HRMS (ESI) m/z calcd for C₂₉H₃₄N₃O₅F₂ (M+H)⁺542.2467, found 542.2460; Anal. Calcd for C₂₉H₃₃N₃O₅F₂.0.75H₂O: C,62.75; H, 6.26; N, 7.57. Found: C, 62.77; H, 6.14; N, 7.37.

EXAMPLE C5(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-pyrrolidine-2-carboxylicacid 3-fluoro-2-methyl-benzylamide

White solid; IR (neat, cm⁻¹) 3310, 1648, 1584, 1531, 1467, 1361, 1284,1101; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.43 (t, J=5.5, 1H), 8.16 (d,J=7.5, 1H), 7.31-6.90 (m, 9H), 6.76 (d, J=8.2, 1H), 6.54 (d, J=7.3, 1H),5.33 (d, J=8.9, 1H), 4.67 (d, J=5.7, 1H), 4.64 (d, J=5.7, 1H), 4.38-4.17(m, 5H), 2.90-2.60 (m, 4H), 2.14 (s, 3H), 1.79 (s, 3H); HRMS (ESI) m/zcalcd for C₃₁H₃₃N₃O₅F₃ (M+H)⁺ 584.2372, found 584.2397; Anal. Calcd forC₃₁H₃₂N₃O₅F₃.1H₂O: C, 62.83; H, 5.61; N, 7.09. Found: C, 62.52; H, 5.63;N, 6.76.

EXAMPLE C6(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-pyrrolidine-2-carboxylicacid 5-fluoro-2-methyl-benzylamide

White solid; IR (neat, cm⁻¹) 3310, 1651, 1585, 1531, 1455, 1372, 1283,1099; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.45 (t, J=5.5, 1H), 8.15 (d,J=7.5, 1H), 7.30-6.90 (m, 9H), 6.76 (d, J=8.2, 1H), 6.55 (d, J=7.7, 1H),5.54 (d, J=6.2, 1H), 4.68 (d, J=5.6, 1H), 4.65 (d, J=5.6, 1H), 4.40-4.00(m, 5H), 3.00-2.60 (m, 4H), 2.19 (s, 3H), 1.79 (s, 3H); HRMS (ESI) m/zcalcd for C₃₁H₃₃N₃O₅F₃ (M+H)⁺ 584.2372, found 584.2391; Anal. Calcd forC₃₁H₃₂N₃O₅F₃.1H₂O: C, 62.83; H, 5.61; N, 7.09. Found: C, 62.73; H, 5.65;N, 6.77.

EXAMPLE C74,4-Difluoro-1-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid propylamide

¹H-NMR (400 MHz, dmso-d⁶): δ 9.30 (s, 1H), 8.13 (d, 1H), 7.87 (t, 1H),7.35-7.08 (m, 5H), 6.91 (t, 1H), 6.74 (d, 1H), 6.52 (d, 1H), 5.44 (d,1H), 4.57 (m, 1H), 4.35-4.09 (m, 3H), 2.96 (m, 2H), 2.83 (d, 1H), 2.7(m, 2H), 2.35 (m, 1H), 1.8 (s, 3H), 1.35 (q, 2H), 0.78 (t, 3H); IR (KBrin cm⁻¹): 3301, 1641, 1524, 1284; MS (APCI, m/z): 504 (M+H), 486, 312,179.

EXAMPLE C8(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-pyrrolidine-2-carboxylicacid ((E)-2-methyl-but-2-enyl)-amide

White solid; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.13 (d, J=7.9, 1H), 8.02(t, J=6.0, 1H), 7.33-7.13 (m, 5H), 6.93 (t, J=7.9, 1H), 6.76 (d, J=8.1,1H), 6.54 (d, J=7.5, 1H), 5.49 (d, J=6.0, 1H), 5.29 (m, 1H), 4.60 (dd,J=9.3, 5.5, 1H), 4.33-4.16 (m, 4H), 3.66 (dd, J=15.2, 5.5, 1H), 3.52(dd, J=15.2, 5.5, 1H), 2.86-2.66 (m, 3H), 2.37 (dd, J=14.5, 5.5, 1H),1.79 (s, 3H), 1.50 (s, 6H); HRMS (ESI) m/z calcd for C₂₈H₃₄N₃O₅F₂ (M+H)⁺530.2467, found 530.2464.

EXAMPLE C9(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-pyrrolidine-2-carboxylicacid (3-methyl-but-2-enyl)-amide

White solid; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.15 (d, J=8.2, 1H), 7.97(t, J=5.5, 1H), 7.35-7.14 (m, 5H), 6.94 (t, J=7.7, 1H), 6.76 (d, J=8.2,1H), 6.53 (d, J=6.8, 1H), 5.47 (d, J=6.6, 1H), 5.07 (m, 1H), 4.57 (dd,J=9.2, 5.3, 1H), 4.32-4.15 (m, 4H), 3.70-3.60 (m, 2H), 2.86-2.64 (m,3H), 2.38 (dd, J=14.1, 5.1, 1H), 1.79 (s, 3H), 1.62 (s, 3H), 1.58 (s,3H); HRMS (ESI) m/z calcd for C₂₈H₃₄N₃O₅F₂ (M+H)⁺ 530.2467, found530.2463.

EXAMPLE C104,4-Difluoro-1-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid 2-chloro-benzylamide

¹H-NMR (400 MHz, dmso-d⁶): 9.35 (s, 1H), 9.3 (d, 1H), 8.52 (t, 1H), 8.13(d, 1H), 7.44-7.09 (m, 9H), 6.91 (t, 1H), 6.74 (d, 1H), 6.48 (d, 1H),5.35 (d, 1H), 4.65 (m, 1H), 4.44-4.17 (m, 5H), 2.96-2.57 (m, 3H), 2.41(m, 1H), 1.74 (s, 3H); IR (KBr, cm⁻¹): 3300, 1640, 1522, 1283; MS (APCI,m/z): 586, 588 (M+H), 445, 330, 284.

EXAMPLE C114,4-Difluoro-1-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid (benzo[1,3]dioxol-5-ylmethyl)-amide

¹H-NMR (400 MHz, dmso-d⁶): δ 9.35 (s, 1H), 8.38 (t, 1H), 8.13 (d, i1H),7.35-7.09 (m, 5H), 6.91 (t, 1H), 6.74 (m, 4H), 6.52 (d, 1H), 5.91 (d,2H), 5.52 (d, 1H), 4.61 (m, 1H), 4.17-4.38 (m, 4H), 4.09 (dd, 1H), 2.87(d, 1H), 2.70 (q, 2H), 2.38 (dd, 1H), 0.78 (s, 3H); IR (KBr, cm⁻¹):3299, 1643, 1492, 1445, 1237, 1038; MS (APCI, m/z): 531 (M+H), 340, 225,180; HPLC: R_(f) (min.) 18.226; Purity: 95%.

EXAMPLE C12(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid 3-methoxy-benzylamide

Isolated material was subjected to flash silica gel chromatography,eluting with 30% EtOAc/hexanes then with EtOAc/hexanes (4:1) to affordthe title compound. Isolated yield: 89%. ¹H NMR (400 MHz, DMSO-d₆): δ9.36 (s, 1H), 8.45 (t, 1H), 8.13 (d, 1H), 7.29 (d, 2H), 7.24-7.19 (m,3H), 7.17-7.14 (m, 2H), 6.92 (t, 1H), 6.82-6.80 (m, 2H), 6.76-6.73 (m,1H), 6.54 (d, 1H), 5.60-5.50 (m, 1H), 4.64 (dd, 1H), 4.37-4.13 (m, 6H),3.69 (s, 3H), 2.88-2.67 (m, 3H), 2.41 (dd, 1H), 1.79 (s, 3H); MS-APCI(m/z+): 582. Anal. C₃₁H₃₃N₃O₆F₂.0.2H₂O calcd: 63.62, 5.75, 7.18; found:63.62, 5.93, 6.92.

EXAMPLE C13(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid 4-methoxy-benzylamide

Isolated material was subjected to flash silica gel chromatography,eluting with EtOAc/hexanes (1:1) then with EtOAc/hexanes (4:1) to affordthe title compound. Isolated yield: 91%. ¹H NMR (400 MHz, DMSO-d₆): δ9.36 (s, 1H), 8.40 (t, 1H), 8.14 (d, 1H), 7.30 (d, 2H), 7.21 (d, 2H),7.17-7.14 (m, 3H), 6.92 (t, 1H), 6.82-6.80 (m, 2H), 6.76-6.73 (m, 1H),6.54 (d, 1H), 5.60-5.50 (m, 1H), 4.64 (dd, 1H), 4.37-4.13 (m, 6H), 3.69(s, 3H), 2.88-2.67 (m, 3H), 2.41 (dd, 1H), 1.79 (s, 3H); MS-APCI (m/z+):582. HPLC: Rf (min.) 18.53; Purity: 100%.

EXAMPLE C14(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid 2-chloro-6-fluoro-benzylamide

Isolated material was subjected to flash silica gel chromatography,eluting with EtOAc/hexanes gradient then with 2% MeOH/CH₂Cl₂ to affordthe title compound. Isolated yield: 49%. ¹H NMR (400 MHz, DMSO-d₆): δ9.38 (s, 1H), 8.38 (t, 1H), 8.36 (d, 1H), 7.38-7.29 (m, 3H), 7.25-7.13(m, 5H), 6.93 (t, 1H), 6.75 (d, 1H), 6.53 (d, 1H), 5.37 (d, 1H), 4.62(dd, 1H), 4.47-4.18 (m, 6H), 2.90-2.64 (m, 3H), 2.35-2.26 (m, 1H), 1.78(s, 3H); MS-APCI (m/z+): 312, 604. HPLC: Rf (min.) 19.02; Purity: 94%;Anal. C₃₀H₂₉N₃O₅F₂Cl₁.0.2H₂O calcd: 59.30, 4.88, 6.92, found 59.27,4.74, 6.69.

EXAMPLE C15(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid 2-methyl-benzylamide

¹H NMR (400 MHz, DMSO-d₆): δ 9.36 (s, 1H), 8.30 (t, 1H), 8.17 (d, 1H),7.33-7.10 (m, 9H), 6.93 (t, 1H), 6.76 (d, 1H), 6.53 (d, 1H), 5.51 (d,1H), 4.50-4.25 (m, 6H), 4.15 (dd, 1H), 2.86 (d, 1H), 2.68 (t, 1H), 2.26(s, 3H), 1.79 (s, 3H), 1.18 (s, 3H), 1.01 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆): δ−107.5 (dt, 1F), −114.2 (d, 1F); MS-APCI (m/z+): 594; HPLCPurity: 97%.: Rf (min.) 19.47; Anal. C₃₃H₃₇N₃O₅F₂.0.2H₂O calcd: C,66.36, H, 6.31, N, 7.04, found: C, 66.30, H, 6.38, N, 6.75.

EXAMPLE C16(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid (S)-indan-1-ylamide

¹H NMR (400 MHz, DMSO-d₆): δ 9.36 (s, 1H), 8.30 (d, 1H), 8.20 (d, 1H),7.32 (d, 2H), 7.24-7.12 (m, 7H), 6.93 (t, 1H), 6.76 (d, 1H), 6.53 (d,1H), 5.45 (d, 1H), 5.29 (dd, 1H), 4.46 (dd, 1H), 4.38-4.20 (m, 4H),2.98-2.74 (m, 3H), 2.67 (t, 1H), 2.42-2.32 (m, 1H), 1.86-1.80 (m, 1H),1.78 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆):δ−109.1 (d, 1F), −113.5 (d, 1F); MS-APCI (m/z+): 606; HPLC Purity: 95%,Rf (min.) 21.30; Anal. C₃₄H₃₇N₃O₅F₂.0.4H₂O calcd: C, 66.63, H, 6.22, N,6.86, found: C, 66.62, H, 6.19, N, 6.79.

EXAMPLE C17(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid prop-2-ynylamide

The title compound was purified by flash chromatography eluting with 0to 5% MeOH/CH₂Cl₂, another column was run which was eluted with 50 to100% ethyl acetate/hexanes. ¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (s, 1H),8.40 (t, 1H), 8.13 (d, 1H), 7.32 (d, 2H), 7.24 (t, 2H), 7.15 (t, 1H),6.93 (t, 1H), 6.75 (d, 1H), 6.51 (d, 1H), 5.54 (d, 1H), 4.43 (dd, 1H),4.36-4.22 (m, 3H), 4.20 (s, 1H), 3.86 (m, 2H), 3.11 (s, 1H), 2.85 (d,1H), 2.67 (t, 1H), 1.77 (s, 3H), 1 .18 (s, 3H), 1.02 (s, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆): δ−108.0 (d, 1F), −114.5 (d, 1F); MS-APCI (m/z+):528, 312; HPLC: Rf (min.) 18.00; Purity: 97%. Anal. C₂₈H₃₁N₃O₅F₂ C, H, Ncalcd: C, 63.75, H, 5.92, N, 7.96, found: C, 63.67, H, 6.21, N, 7.85.

EXAMPLE C18(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-3,3-dimethyl-pyrrolidine-2-carboxylicacid 2-chloro-4-fluoro-benzylamide

Isolated material was subjected preparative HPLC purification, elutingwith EtOAc/hexanes to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆): δ 9.36 (s, 1H), 8.52 (t, 1H), 8.16 (d, 1H), 7.49 (dd, 1H),7.40 (d, 1H), 7.28 (d, 2H), 7.24-7.19 (m, 3H), 7.15-7.10 (m, 2H), 6.92(t, 1H), 6.75 (d, 1H), 6.52 (d, 1H), 5.55 (d, 1H), 4.46 (dd, 1H),4.39-4.24 (m, 5H), 2.84 (d, 1H), 2.69-2.64 (m, 1H), 1.78 (s, 3H), 1.19(s, 3H), 1.00 (s, 3H); MS-APCI (m/z+): 312, 632. HPLC: Rf (min.) 16.83;Purity: 93%.

EXAMPLE C19(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-3,3-dimethyl-pyrrolidine-2-carboxylicacid propylamide

¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (s, 1H), 8.13 (d, 1H), 7.89 (bs, 1H),7.32 (d, 2H), 7.23 (t, 2H), 7.15 (t, 1H), 6.92 (t, 1H), 6.75 (d, 1H),6.51 (d, 1H), 5.48 (d, 1H), 4.40 (dd, 1H), 4.34-4.14 (m, 4H), 3.01 (m,2H), 2.84 (d, 1H), 2.67 (t, 1H), 1.78 (s, 3H), 1.39 (m, 2H), 1.17 (s,3H), 1.01 (s, 3H), 0.83 (t, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−108.3 (d,1F), −114.0 (d, 1F); MS-APCI (m/z+): 532, 312; HPLC Purity: 100%, Rf(min.) 18.22; Anal. C₂₈H₃₅N₃O₅F₂.0.2H₂O calcd, C, 62.84, H, 6.67, N,7.85, found: C, 62.71, H, 6.65, N, 7.64.

EXAMPLE C20(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid (furan-2-ylmethyl)-amide

¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (s, 1H), 8.40 (t, 1H), 8.13 (d, 1H),7.54 (s, 1H), 7.32 (d, 2H), 7.24 (t, 2H), 7.15 (t, 1H), 6.93 (t, 1H),6.75 (d, 1H), 6.52 (d, 1H), 6.36 (s, 1H), 6.25 (s, 1H), 5.53 (d, 1H),4.42 (dd, 1H), 4.36-4.24 (m, 6H), 2.85 (d, 1H), 2.68 (t, 1H), 1.79 (s,3H), 1.16 (s, 3H), 0.97 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−108.2 (d,1F), −114.3 (d, 1F); MS-APCI (m/z+): 570; HPLC: Rf (min.) 18.73; Purity:100%. Anal. C₃₀H₃₃N₃O₆F₂ calcd: C, 63.26, H, 5.84, N, 7.38, found: C,63.35, H, 5.71, N, 7.20.

EXAMPLE C214,4-Difluoro-1-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid isobutyl-amide

¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (s, 1H), 8.14 (d, 1H), 7.90 (t, 1H),7.33 (d, 2H), 7.23 (t, 2H), 7.15 (t, 1H), 6.93 (t, 1H), 6.76 (d, 1H),6.52 (d, 1H), 5.46 (d, 1H), 4.41 (dd, 1H), 4.34-4.20 (m, 4H), 2.92-2.80(m, 3H), 2.67 (t, 1H), 1.78 (s, 3H), 1.67 (m, 1H), 1.18 (s, 3H), 1.02(s, 3H), 0.83 (d, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−108.2 (dt, 1F),−113.9 (d, 1F); MS-APCI (m/z+): 546; HPLC Purity: 100%, Rf (min.) 18.81;Anal. C₂₉H₃₇N₃O₅F₂.0.2H₂O calcd: C, 63.42, H, 6.85, N, 7.65, found: C,63.29, H, 6.77, N, 7.49.

EXAMPLE C22(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid (thiophen-2-ylmethyl)-amide

¹H NMR (400 MHz, DMSO-d₆): δ 9.36 (s, 1H), 8.53 (t, 1H), 8.13 (d, 1H),7.36 (dd, 1H), 7.33 (d, 2H), 7.24 (t, 2H), 7.15 (t, 1H), 6.97 (t, 1H),6.92 (m, 2H), 6.76 (d, 1H), 6.53 (d, 1H), 5.53 (d, 1H), 4.49-4.26 (m,6H), 4.23 (s, 1H), 2.88 (d, 1H), 2.69 (dd, 1H), 1.79 (s, 3H), 1.17 (s,3H), 1.00 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−108.6 (dt, 1F), −114.2(d, 1F); MS-APCI (m/z+): 586; HPLC Purity: 100%, Rf (min.) 19.07; Anal.C₃₀H₃₃N₃O₅F₂S calcd: C, 61.52, H, 5.68, N, 7.17, found: C, 61.23, H,5.64, N, 6.90.

EXAMPLE C23(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid (2,2,2-trifluoro-ethyl)-amide

¹H NMR (400 MHz, DMSO-d₆): δ 9.35 (s, 1H), 8.66 (t, 1H), 8.14 (d, 1H),7.31 (d, 2H), 7.24 (t, 2H), 7.15 (t, 1H), 6.93 (t, 1H), 6.75 (d, 1H),6.51 (d, 1H), 5.56 (d, 1H), 4.45 (dd, 1H), 4.38-4.25 (m, 4H), 4.04-3.94(m, 1H), 3.90-3.80 (m, 1H), 2.85 (d, 1H), 2.66 (dd, 1H), 1.77 (s, 3H),1.19 (s, 3H), 1.01 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−71.0 (t, J=10Hz, 3F), −108.0 (dm, J=227 Hz, 1F), −114.6 (d, J=227 Hz, 1F); MS-APCI(m/z+): 572, 312; HPLC Purity: 100%, Rf (min.) 18.98; Anal. C₂₇H₃₀N₃O₅F₅calcd: C, 56.74, H, 5.29, N, 7.35, found: C, 56.56, H, 5.43, N, 7.15.

EXAMPLE C24(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid (S)-1-benzopyran-4-y

Isolated material was subjected to flash silica gel chromatography,eluting with 45% EtOAc/hexanes to afford the title compound. ¹H NMR (400MHz, DMSO-d₆): δ 9.35 (s, 1H), 8.47 (d, 1H), 8.20 (d, 1H), 7.33 (d, 2H),7.23 (t, 2H), 7.17-7.12 (m, 3H), 6.93 (t, 1H), 6.87 (t, 1H), 6.79 (t,2H), 6.53 (d, 1H), 5.40 (d, 1H), 4.96 (dd, 1H), 4.47 (dd, 1H), 4.34-4.14(m, 6H), 2.82 (d, 1H), 2.67 (t, 1H), 2.03-1.98 (m, 1H), 1.93-1.89 (m,1H), 1.79 (s, 3H), 1.17 (s, 3H), 1.12 (s, 3H); MS-APCI (m/z+): 622.HPLC: Rf (min.) 19.65; Purity: 94%; C₃₄H₃₇N₃O₆F₂.0.5H₂O calcd: 64.75,6.07, 6.66, found: 64.77, 6.24, 6.54.

EXAMPLE C25(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid 4-methoxy-benzylamide

Isolated material was subjected to flash silica gel chromatography,eluting with 45% EtOAc/hexanes to afford the title compound. ¹H NMR (400MHz, DMSO-d₆): δ 9.36 (s, 1H), 8.34 (t, 1H), 8.13 (d, 1H), 7.31 (d, 2H),7.25-7.13 (m, 5H), 6.93 (t, 1H), 6.83 (d, 2H), 6.76 (d, 1H), 6.53 (d,1H), 5.54 (d, 1H), 4.43 (dd, 1H), 4.34-4.25 (m, 5H), 4.13 (dd, 1H), 3.68(s, 3H), 2.88 (d, 1H), 2.68 (dd, 1H), 1.79 (s, 3H), 1.17 (s, 3H), 0.99(s, 3H); MS-APCI (m/z+): 610; C₃3H₃₇N₃O₆F₂.0.4H₂O calcd: 64.25, 6.18,6.81, found: 64.19, 6.13, 6.73.

EXAMPLE C26(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid (1,3-benzodioxol-5-ylmethyl)-amide

Isolated material was subjected to flash silica gel chromatography,eluting with 45% EtOAc/hexanes to afford the title compound. ¹H NMR (400MHz, DMSO-d₆): δ 9.33 (s, 1H), 8.35 (t, 1H), 8.12 (d, 1H), 7.29 (d, 2H),7.21 (t, 2H), 7.12 (t, 1H), 6.91 (t, 1H), 6.81-6.71 (m, 4H), 6.51 (d,1H), 5.91 (d, 2H), 5.53 (d, 1H), 4.43 (dd, 1H), 4.30-4.23 (m, 5H), 4.07(dd, 1H), 2.86 (d, 1H), 2.66 (t, 1H), 1.77 (s, 3H), 1.16 (s, 3H), 0.98(s, 3H); MS-APCI (m/z+): 135, 312, 624. HPLC: Rf (min.) 19.00; Purity:97%; C₃₃H₃₅N₃O₇F₂.0.6H₂O calcd: 62.47, 5.75, 6.62, found, 62.41, 5.65,6.36.

EXAMPLE C27(S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-oxazolidine-4-carboxylicacid (S)-indan-1-ylamide

¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.3-1 (d, J=8. 1, 1H), 8.13 (d, J=9.0,1H), 7.30-7.13 (m, 9H), 6.94 (t, J=7.9, 1H), 6.76 (d, J=7.9, 1H), 6.55(d, J=7.5, 1H), 5.72 (d, J=6.2, 1H), 5.46 (d, J=4.0, 1H), 5.31 (dd,J=15.6, 7.7, 1H), 5.24 (d, J=3.9, 1H), 4.36 (m, 1H), 4.19 (m, 1H), 4.16(s, 1H), 2.94-2.64 (m, 4H), 2.41-2.34 (m, 1H), 1.86-1.77 (m, 1H), 1.77(s, 3H), 1.29 (s, 3H), 1.27 (s, 3H); HRMS (ESI) m/z calcd for C₃₃H₃₈N₃O₆(M+H)⁺ 572.2761, found 572.2768.

EXAMPLE C28(4S,5S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5-methyl-oxazolidine-4-carboxylicacid (S)-cyclohex-2-enylamide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.12 (d, J=8.2, 1H), 7.92 (d, J=8.2,1H), 7.31-7.13 (m, 5H), 6.94 (t, J=7.9, 1H), 6.76 (d, J=7.9, 1H), 6.56(d, J=7.3, 1H), 5.77-5.73 (m, 1H), 5.66 (d, J=6.4, 1H), 5.51 (d, J=3.7,1H), 5.50-5.44 (m, 1H), 5.06 (d, J=3.7, 1H), 4.40-4.15 (m, 5H),2.97-2.65 (m, 2H), 1.94 (m, 2H), 1.79-1.67 (m, 2H), 1.77 (s, 3H),1.57-1.44 (m, 2H), 1.20 (d, J=6.2, 3H); HRMS (ESI) m/z calcd forC₂₉H₃₆N₃O₆ (M+H)⁺ 522.2604, found 522.2623.

EXAMPLE C29(S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-oxazolidine-4-carboxylicacid (S)-cyclohex-2-enylamide

¹H NMR (DMSO-d₆) δ 9.36 (s br, 1H), 8.11 (d, J=8.6, 1H), 7.97 (d, J=7.9,1H), 7.32-7.15 (m, 5H), 6.93 (t, J=7.7, 1H), 6.76 (d, J=8.1, 1H), 6.54(d, J=7.3, 1H), 5.76 (m, 1H), 5.67 (d, J=6.4, 1H), 5.54-5.41 (m, 1H),5.43 (d, J=3.8, 1H), 5.21 (d, J=3.8, 1H), 4.40-4.28 (m, 2H), 4.19-4.14(m, 2H), 2.88 (m, 1H), 2.70 (m, 1H), 1.95 (m, 2H), 1.78 (s, 3H),1.82-1.68 (m, 2H), 1.58-1.45 (m, 2H), 1.28 (s, 3H), 1.22 (s, 3H); HRMS(ESI) m/z calcd for C₃₀H₃₈N₃O₆ (M+H)⁺ 536.276 1, found 536.275 1; Anal.Calcd for C₃₀H₃₇N₃O₆: C, 67.27; H, 6.96; N, 7.85. Found: C, 67.07; H,7.00; N, 7.71.

EXAMPLE C303-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-1-thia-3-aza-spiro[4.4]nonane-4-carboxylicacid 2-methyl-benzamide

White solid; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.38 (t, J=5.5, 1H), 8.26(d, J=8.1, 1H), 7.31-6.85 (m, 10H), 6.76 (d, J=8.1, 1H), 6.53 (d, J=7.7,1H), 5.54 (d, J=6.4, 1H), 5.12 (d, J=9.2, 1H), 4.95 (d, J=9.2, 1H), 4.55(s, 1H), 4.50-4.10 (m, 3H), 4.01 (m, 1H), 2.90-2.60 (m, 2H), 2.20 (s,3H), 2.10-1.85 (m, 4H), 1.81 (s, 3H), 1.80-1.50 (m, 4H); Anal. Calcd forC₃₄H₃₉N₃O₅S: C, 67.86; H, 6.53; N, 6.98. Found: C, 67.50; H, 6.23; N,6.70.

EXAMPLE C313-(2-Hydroxy-3-{[1-(2-methyl-3-hydroxy-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-1-thia-3-aza-spiro[4.5]decane-4-carboxylicacid 2-methyl-benzylamide

White solid; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.36 (t, J=5.5, 1H), 8.28(d, J=8.1, 1H), 7.34-6.83 (m, 10H), 6.74 (d, J=8.1, 1H), 6.60 (d, J=7.7,1H), 5.57 (d, J=6.4, 1H), 5.09 (d, J=9.2, 1H), 4.97 (d, J=9.2, 1H), 4.65(s, 1H), 4.55-4.06 (m, 3H), 4.01 (m, 1H), 2.91-2.50 (m, 2H), 2.22 (s,3H), 2.10-1.83 (m, 5H), 1.80 (s, 3H), 1.78-1.50 (m, 5H); Anal. Calcd forC₃₅H₄₁N₃O₅S: C, 68.26; H, 6.71; N, 6.82. Found: C, 68.44; H, 6.53; N,6.73.

EXAMPLE C327-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5-thia-7-aza-spiro[3.4]octane-8-carboxylicacid-2-methyl benzylamide

White solid; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.40 (t, J=5.5, 1H), 8.33(d, J=8.1, 1H), 7.34-6.92 (m, 10H), 6.81 (d, J=8.1, 1H), 6.51 (d, J=7.7,1H), 5.48 (d, J=6.4, 1H), 5.09 (d, J=9.2, 1H), 4.87 (d, J=9.2, 1H), 4.63(s, 1H), 4.58-4.17 (m, 3H), 4.05 (m, 1H), 2.89-2.62 (m, 2H), 2.26 (s,3H), 2.13-1.86 (m, 3H), 1.80 (s, 3H), 1.79-1.50 (m, 3H); Anal. Calcd forC₃₃H₃₇N₃O₅S: C, 67.44; H, 6.35; N, 7.15. Found: C, 67.57; H, 6.13; N,7.22.

EXAMPLE C33(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-1-thia-3-aza-spiro[4.4]nonane-4-carboxylicacid propylamide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.11 (d, J=8.4, 1H), 7.86 (t, J=5.5,1H), 7.34-7.13 (m, 5H), 6.93 (t, J=7.7, 1H), 6.80 (d, J=8.1, 1H), 6.52(d, J=7.3, If), 5.44 (d, J=7.0, 1H), 5.08 (d, J=9.0, 1H), 4.95 (d,J=9.3, 1H), 4.47 (s, 1H), 4.44 (m, 2H), 3.04-2.95 (m, 2H), 2.85-2.70 (m,2H), 1.93 (m, 2H), 1.81-1.61 (m, 6H), 1.80 (s, 3H), 1.31 (m, 2H), 0.82(t, J=7.3, 31H); HRMS (ESI) m/z calcd for C₂₉H₃₈N₃O₅S (M+H)⁺ 540.2532,found 540.2531.

EXAMPLE C34(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-1-thia-3-aza-spiro[4.4]nonane-4-carboxylicacid ((E)-2-methyl-but-2-enyl)-amide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.08 (d, J=8.1, 1H), 7.92 (t, J=5.7,1H), 7.33-7.15 (m, 5H), 6.93 (t, J=7.7, 1H), 6.77 (d, J=8.1, 1H), 6.53(d, J=7.3, 1H), 5.48 (d, J=6.2, 1H), 5.32 (m, 1H), 5.08 (d, J=9.3, 1H),4.92 (d, J=9.2, 1H), 4.49 (s, 1H), 4.43 (m, 2H), 3.74-3.67 (m, 1H), 3.42(m, 1H), 2.85-2.72 (m, 2H), 1.98-1.90 (m, 2H), 1.82-1.62 (m, 6H), 1.81(s, 3H), 1.49 (s, 6H); HRMS (ESI) m/z calcd for C₃₁H₄₀N₃O₅S (M+H)⁺566.2689, found 566.2685.

EXAMPLE C35(S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-1-thia-3-aza-spiro[4.4]nonane-4-carboxylicacid (S)-cyclohex-2-enylamide

¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.15 (d, J=8.4, 1H), 7.91 (d, J=7.9,1H), 7.34-7.12 (m, 5H), 6.96-6.91 (m, 1H), 6.76 (d, J=8.1, 1H), 6.53 (d,J=7.5, 1H), 5.80-5.65 (m, 1H), 5.48-5.40 (m, 1H), 5.36 (d, J=7.2, 1H),5.10 (d, J=9.2, 1H), 4.94 (d, J=9.2, 1H), 4.54 (s, 1H), 4.50-4.20 (m,3H), 2.90-2.60 (m, 2H), 2.10-1.82 (m, 4H), 1.79 (s, 3H), 1.78-1.40 (m,10H); Anal. Calcd for C₃₂H₃₉N₃O₅S: C, 66.53; H, 6.80; N, 7.27. Found: C,66.34; H, 6.62; N, 6.96.

EXAMPLE C36(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-1-thia-3-aza-spiro[4.4]nonane-4-carboxylicacid 5-fluoro-2-methyl-benzylamide

White solid; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.38 (t, J=5.5, 1H), 8.26(d, J=8.1, 1H), 7.31-6.85 (m, 9H), 6.76 (d, J=8.1, 1H), 6.53 (d, J=7.7,1H), 5.54 (d, J=6.4, 1H), 5.12 (d, J=9.2, 1H), 4.95 (d, J=9.2, 1H), 4.55(s, 1H), 4.50-4.10 (m, 3H), 4.01 (dd, J=16.0, 5.5, 1H), 2.90-2.60 (m,2H), 2.20 (s, 3H), 2.10-1.85 (m, 4H), 1.81 (s, 3H), 1.80-1.50 (m, 4H);Anal. Calcd for C₃₄H₃₈N₃O₅SF: C, 65.51; H, 6.21; N, 6.74. Found: C,65.50; H, 6.23, N, 6.70.

EXAMPLE C37(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-1-thia-3-aza-spiro[4.4]nonane-4-carboxylicacid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide

White solid; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.26 (d, J=8.4, 1H), 8.20(d, J=8.4, 1H), 7.30-6.89 (m, 10H), 6.76 (d, J=8.1, 1H), 6.54 (d, J=7.3,1H), 5.36 (d, J=6.8, 1H), 5.12 (d, J=9.2, 1H), 4.98-4.90 (m, 2H),4.60-4.30 (m, 3H), 2.90-2.60 (m, 4H), 2.07 (s, 3H), 2.05-1.50 (m, 12H);Anal. Calcd for C₃₆H₄₁N₃O₅S: C, 68.87; H, 6.58; N, 6.69. Found: C,68.80; H, 6.41; N, 6.60.

EXAMPLE C38(R)-7-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5-thia-7-aza-spiro[3.4]octane-8-carboxylicacid propylamide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.11 (d, J=8.4, 1H), 7.96 (t, J=5.9,1H), 7.33-7.13 (m, 5H), 6.93 (t, J=7.9, 1H), 6.76 (d, J=7.3, 1H), 6.53(d, J=7.5, 1H), 5.41 (d, J=6.9, 1H), 4.96 (d, J=9.3, 1H), 4.92 (d,J=9.5, 1H), 4.50 (s, 1H), 4.45 (d, J=5.1, 1H), 4.37 (m, 1H), 3.03 (m,2H), 2.82-2.66 (m, 2H), 2.56-2.42 (m, 2H), 2.16-1.80 (m, 4H), 1.80 (s,3H), 1.39 (m, 2H), 0.82 (t, J=7.5, 3H); HRMS (ESI) m/z calcd forC₂8H₃₆N₃O₅S (M+H)⁺ 526.2376, found 526.2375.

EXAMPLE C39(R)-7-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5-thia-7-aza-spiro[3.4]octane-8-carboxylicacid (S)-cyclohex-2-enylamide

White solid; ¹H NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.18 (d, J=8.2, 1H), 8.07(d, J=8.1, 1H), 7.36-7.18 (m, 5H), 6.96 (t, J=8.2, 1H), 6.79 (d, J=8.3,1H), 6.56 (d, J=7.1, 1H), 5.77 (m, 1H), 5.56-5.47 (m, 1H), 5.36 (d,J=7.0, 1H), 5.02 (d, J=9.3, 1H), 4.95 (d, J=9.3, 1H), 4.58 (s, 1H), 4.51(m, 1H), 4.39-4.31 (m, 2H), 2.75-2.70 (m, 2H), 2.60-2.44 (m, 2H), 2.15(m, 1H), 2.04-1.88 (m, 5H), 1.82 (s, 3H), 1.80-1.64 (m, 2H), 1.55-1.46(m, 2H); HRMS (ESI) m/z calcd for C₃₁H₃₈N₃O₅S (M+H)⁺ 564.2532, found564.2523.

EXAMPLE C401-{3-[2-(2,6-Dimethyl-phenoxy)-acetylamino]-2-hydroxy-4-phenyl-butyryl}-4,4-difluoro-pyrrolidine-2-carboxylicacid 2-methyl-benzylamide

¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (t, 1H), 8.13 (d, 1H), 7.29 (d, 2H),7.25-7.08 (m, 7H), 6.99 (d, 2H), 6.91 (dd, 1H), 5.53 (d, 1H), 4.66 (dd,1H), 4.33-4.10 (m, 7H), 3.94 (d, 1H), 2.86-2.73 (m, 4H), 2.46-2.38 (m,1H), 2.22 (s, 3H), 2.12 (s, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−98.1 (dq,1F), −100.0 (dq, 1F); MS-APCI (m/z+): 594; HPLC Purity: 100%, Rf (min.)21.97; Anal. C₃₃H₃₇N₃O₅F₂.0.3H₂O calcd: C, 66.16, H, 6.33, N, 7.01;found: C, 66.23, H, 6.57, N, 7.12.

EXAMPLE C41{(1S,2S)-1-Benzyl-3-[(S)-4,4-difluoro-2-(2-methyl-benzylcarbamoyl)-pyrrolidin-1-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid (S)-(tetrahydro-furan-3-yl)ester

White solid; ¹H NMR (DMSO-d₆) δ 8.34 (t, J=5.5, 1H), 7.31-7.09 (m, 10H),5.40 (d, J=7.0, 1H), 4.95 (m, 1H), 4.65 (dd, J=9.2, 5.7, 1H), 4.35-4.09(m, 5H), 3.81 (m, 1H), 3.75-3.56 (m, 3H), 3.40 (d, J=10.0, 1H),2.80-2.36 (m, 4H), 2.23 (s, 3H), 2.05-1.95 (m, 1H), 1.81 (m, 1H); HRMS(ESI) m/z calcd for C₂₈H₃₄N₃O₆F₂ (M+H)⁺ 546.2416, found 546.2418.

EXAMPLE C42(S)-4,4-Difluoro-1-((2S,3S)-2-hydroxy-3-{[1-(3-hydroxy-2,4-dimethyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-pyrrolidine-2-carboxylicacid 2-methyl-benzylamide

White solid; ¹H NMR (DMSO-d₆) δ 8.35 (t, J=5.7, 1H), 8.25 (s br, 1H),8.09 (d, J=7.9, 1H), 7.33-7.08 (m, 9H), 6.85 (d, J=7.7, 1H), 6.53 (d,J=7.5, 1H), 5.49 (d, J=6.2, 1H), 4.67 (dd, J=9.3, 5.5, 1H), 4.35-4.14(m, 6H), 2.86-2.67 (m, 4H), 2.23 (s, 3H), 2.13 (s, 3H), 1.85 (s, 3H);HRMS (ESI) m/z calcd for C₃₂H₃₆N₃O₅F₂ (M+H)⁺ 580.2623, found 580.2650.

EXAMPLE C43 3,5-Dimethyl-isoxazole-4-carboxylic acid{1-benzyl-3-[4,4-difluoro-2-(2-methyl-benzylcarbamoyl)-pyrrolidin-1-yl]-2-hydroxy-3-oxo-propyl}-amide

The crude was purified by chromatography eluted with 10% and 20% acetonein CH₂Cl₂. ¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (t, 1H), 8.13 (d, 1H), 7.29(d, 2H), 7.24-7.09 (m, 7H), 5.54 (d, 1H), 4.66 (dd, 1H), 4.40 (dd, 1H),4.34-4.28 (m, 3H), 4.25-4.18 (m, 2H), 2.87-2.68 (m, 3H), 2.43-2.36 (m,1H), 2.25 (s, 3H), 2.22 (s, 3H), 2.07 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆): δ−98.0 (dq, 1F), −99.9 (dq, 1F); MS-APCI (m/z+): 555; ; HPLCPurity: 100%, Rf (min.) 19.63; Anal. C₂₉H₃₂N₄O₅F₂.0.3H₂O calcd: C,62.20, H, 5.87, N, 10.00; found: C, 62.25, H, 6.00, N, 9.65.

EXAMPLE C44{1-Benzyl-3-[4,4-difluoro-2-(2-methyl-benzylcarbamoyl)-pyrrolidin-1-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid prop-2-ynyl ester

The crude was purified by chromatography eluted with 10% acetone inCH₂Cl₂. ¹H NMR (400 MHz, DMSO-d₆): δ 8.37 (t, 1H), 7.53 (d, 1H), 7.28(d, 2H), 7.24-7.10 (m, 7H), 5.36 (d, 1H), 4.65 (dd, 1H), 4.54-4.42 (m,2H), 4.35-4.18 (m, 4H), 4.11 (dd, 1H), 3.8 (m, 1H), 3.43 (t, 1H),2.79-2.69 (m, 2H), 2.59 (dd, 1H), 2.42-2.34 (m, 1H); ¹⁹F NMR (376 MHz,DMSO-d₆): δ−98.2 (dq, 1F), −99.7 (dq, 1F); MS-APCI (m/z+): 514; HPLCPurity: 92%, Rf (min.) 19.80; Anal. C₂₇H₂₉N₃O₅F₂ calcd: C, 63.15, H,5.69, N, 8.18; found: C, 63.00, H, 6.02, N, 8.02.

EXAMPLE C451-{3-[2-(2,6-Dimethyl-phenoxy)-acetylamino]-2-hydroxy-4-phenyl-butyryl}-4,4-difluoro-pyrrolidine-2-carboxylicacid propylamide

¹H-NMR (400 MHz, dmso-d⁶): 8.09 (d, 1H), 7.91 (t, 1H), 6.8-7.35 (m, 8H),5.48 (d, 1H), 4.6 (m, 1H), 3.87-4.4 (m, 5H), 3.04 (d, 2H), 2.61-2.87 (m,3H), 2.35 (m, 1H), 2.35 (s, 3H), 2.13 (s, 6H), 1.4 (q, 2H), 0.8 (t, 3H);IR (KBr in cm−1): 3278, 2931, 1657, 1534, 1449, 1194; MS (APCI, m/z):531 (M+H), 340, 225, 180; HPLC: R_(f) (min.) 20.57; Purity: 95%.

EXAMPLE C46(S)-1-{(2S,3S)-3-[2-(2,6-Dimethyl-phenoxy)-acetylamino]-2-hydroxy-4-phenyl-butyryl}-4,4-difluoro-3,3-dimethyl-pyrrolidine-2-carboxylicacid 2-methyl-benzylamide

¹H NMR (400 MHz, DMSO-d₆): δ 8.33 (t, 1H), 8.14 (d, 1H), 7.33-7.28 (m,3H), 7.22 (t, 2H), 7.16 (d, 1H), 7.14-7.06 (m, 3H), 7.02-6.86 (m, 2H),6.91 (t, 1H), 5.50 (d, 1H), 4.36 (dd, 1H), 4.34-4.18 (m, 6H), 4.14 (d,1H), 3.98 (d, 1H), 2.84-2.70 (m, 2H), 2.25 (s, 3H), 2.13 (s, 6H), 1.19(s, 3H), 1.02 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−109.1 (dt, 1F),−113.3 (dt, 1F); MS-APCI (m/z+): 622; HPLC Purity: 94%, Rf (min.) 23.90;Anal. C₃₅H₄₁N₃O₅F₂ calcd: C, 67.62, H, 6.65, N, 6.76, found: C, 67.54,H, 7.02, N, 7.09.

EXAMPLE C47{(1S,2S)-1-Benzyl-3-[(S)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-oxazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-carbamicacid (S)-(tetrahydro-furan-3-yl)ester

¹H NMR (DMSO-d₆) δ 8.29 (t, J=8.7, 1H), 7.25-7.13 (m, 10H), 5.60 (d,J=6.8, 1H), 5.31 (d, J=4.0, 1H), 5.16 (d, J=4.0, 1H), 4.88 (m, 1H),4.47-4.05 (m, 5H), 3.86 (m, 1H), 3.72-3.54 (m, 3H), 2.80 (m, 1H), 2.60(m, 1H), 2.26 (s, 3H), 2.04-1.94 (m, 1H), 1.81-1.76 (m, 1H), 1.29 (s,3H), 1.16 (s, 3H) HRMS (ESI) m/z calcd for C₂₉H₃₈N₃O₇ (M+H)⁺ 540.2710,found 540.2706.

EXAMPLE C481-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-4-oxo-pyrrolidine-2-carboxylicacid 2-methyl-benzylamide

The product was recrystallized from ethyl acetate, ethyl ether andhexanes. ¹H NMR (400 MHz, DMSO-d₆): δ 9.34 (s, 1H), 8.73 (t, 1H), 8.18(d, 1H), 7.26-7.05 (m, 9H), 6.92 (t, 1H), 6.75 (d, 1H), 6.51 (d, 1H),5.56 (d, 1H), 4.75 (s, 1H), 4.55 (d, 1H), 4.40-4.32 (m, 4H), 4.14 (dd,1H), 2.85 (d, 1H), 2.66 (dd, 1H), 2.23 (s, 3H), 1.75 (s, 3H), 1.11 (s,3H), 0.94 (s, 3H); MS-APCI (m/z+): 572; HPLC Purity: 100%, Rf (min.)19.31.

EXAMPLE C49(3S,4aS,8aS)-2-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-decahydro-isoquinoline-3-carboxylicacid 2-methyl-benzylamide

White solid: ¹H NMR (DMSO) δ 9.38 (s, 1H), 8.45-8.15 (m, 2H), 7.40-6.40(m, 12H), 5.18 (d, J=7.0, 1H), 5.00-3.35 (m, 5H), 3.00-1.00 (m, 22H);Anal. Calcd for C₃₆H₄₃N₃O₅.0.25 1120: C, 71.80; 1H, 7.28; N, 6.98.Found: C, 71.83; H, 7.40; N, 7.13.

EXAMPLE C50-2-(2-Hydroxy-3-{[1-(-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-2-aza-bicyclo[2.2.1]-heptane-3-carboxylicacid-2-methyl-benzylamide

¹H NMR (DMSO) δ 9.34 (s, 1H), 8.25-8.17 (m, 2H), 7.40-7.16 (m, 9H), 6.96(q, J=7.7, 1H), 6.80 (d, J=7.7, 1H), 6.58 (d, J=7.7, 1H), 4.91 (d,J=5.7, 1H), 4.74 (s, 1H), 4.46-4.00 (m, 5H), 2.85-2.66 (m, 3H), 2.28 (s,3H), 1.88 (s, 3H), 1.85-1.50 (m, 6H); HRMS (ESI) m/z calcd forC₃₃H₃₇N₃O₅Na (M+Na)⁺ 578.2625, found 578.2604.

The synthesis of compounds with the general structure 27 is as follows.The boc-protected thiazolidine carboxylic acid 1 is converted toamino-ketones 26 with requisite grignard reagents 25 in the presence ofoxalyl chloride. Final compounds 27 are obtained by a DCC-mediatedcoupling of 26 and 4 followed by deprotection of the P2 phenol. Finalcompounds were purified either by flash chromatography or preparativeHPLC.

Specific Method D

EXAMPLE D1N-[(1S,2S)-1-Benzyl-3-((R)-5,5-dimethyl-4-pent-4-enoyl-thiazolidin-3-yl)-2-hydroxy-3-oxo-propyl]-3-hydroxy-2-methyl-benzamide

The title compound was prepared as follows.(R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1(1.0 g, 3.80 mmol) was dissolved in benzene (10 mL) and cooled to 0° C.with magnetic stirring. Two drops of DMF were added followed by a dropwise addition of oxalyl chloride (0.33 mL, 3.80 mmol). When gasevolution ceased, the solution was concentrated to a yellow/red residue.The material was dissolved in dry THF (10 mL) and cooled to −78° C. withmagnetic stirring. The grignard reagent, 3-butenylmagnesium bromide (7.7mL, 3.80 mmol) was added dropwise over 10 min. The result was stirred at−78° C. for 1 h then at −55° C. for 30 min. The reaction was quenched at−55° C. with sat NH₄Cl soln.(3 mL) and then poured into H₂O (50 mL). Themixture was extracted with EtOAc (2×50 mL). The combined organics werewashed with brine (1×100 mL), dried over Na₂SO₄, filtered, andconcentrated. The result was the amino ketone 26 that was sufficientlypure to use in the subsequent step. The clear oil 26 (0.24 g, 1.15 mmol)was dissolved in EtOAc (10 mL). AMB-AHPBA 4 (0.40 g, 1.09 mmol) wasadded followed by HOBt (0.15 g, 1.09 mmol). The mixture was stirred atroom temperature 1 h, then cooled to 0° C. DCC (0.24 g, 1.15 mmol) wasslowly added as solution in EtOAc (6 mL). The mixture was warmed to roomtemperature and stirred overnight. The mixture was filtered and thefiltrate was washed with 1N HCl (10 mL), saturated NaHCO₃ (10 mL), brine(10 mL), dried over Na₂SO₄ and concentrated to give a crude white solid(contaminated with DCU). The DCU was removed by flash chromatography(30% to 50% EtOAc in hexanes) to provide a white solid, which wasdissolved in MeOH (2 mL) and treated with 4N HCl in 1,4-dioxane (0.26mL, 1.1 mmol). The reaction was stirred at room temperature overnightthen partitioned between 1N HCl (10 mL) and EtOAc (10 mL). The organiclayer was washed with saturated sat. NaHCO₃ (1×25 mL) dried over Na₂SO₄,filtered, and concentrated to a residue which was purified by flashchromatography (60% EtOAc in hexanes) to provide the title compound as awhite amorphous solid: ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.23 (d, J=8.1,1H), 7.35-7.14 (m, 5H), 6.96 (t, J=7.5, 1H), 6.78 (d, J=8.2, 1H), 6.52(d, J=7.5, 1H), 5.81-5.69 (m, 2H), 5.32 (d, J=9.7, 1H), 5.11-5.91 (m,3H), 4.40 (m, 3H), 2.89-2.61 (m, 4H), 2.37-2.14 (m, 2H), 1.81 (s, 3H),1.55 (s, 3H), 1.30 (s, 3H); Anal. Calcd for C₂₈H₃₄N₂O₅S: C, 65.86; H,6.71; N, 5.49. Found: C, 65.52; H, 6.55; N, 5.81.

The following examples were synthesized using the specific methodoutlined above using the appropriate grignard reagent for the desiredcompound.

EXAMPLE D2(R)-3-(2S,3R)-4,4-Difluoro-1-[4-(3-fluoro-phenyl)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-butyl])-3,3-dimethyl-pyrrolidine-2-carboxylicacid allylamide

The following represents synthesis of key intermediates for thesynthesis of the title compound.

L-2-tert-Butoxycarbonylamino-3-(3-fluoro-phenyl)-propionic acid.

A mixture of L-2-amino-3-(3-fluoro-phenyl)-propionic acid (20.0 g, 110mmol, 1 eq) in H₂O (100 mL) was treated with Na₂CO₃ (16.2 g, 153 mmol,1.4 eq) in H₂O (40 mL) followed by 1,4-dioxane (100 mL) and cooled to 0°C. The BOC₂O was added and the reaction mixture was stirred at ambienttemperature for 5 h after which the dioxane was evaporated. H₂O (125 mL)was then added and the mixture then washed with Et₂O (2×100 mL). Theaqueous phase was acidified with 10% citric acid followed by extractionwith EtOAc (2×300 mL). The combined EtOAc layers were washed with H₂O(2×150 mL), brine (150 mL), dried (Na₂SO₄) and concentrated to give theacid as a colorless, viscous oil which slowly solidified upon standing(31 g, quant). ¹H NMR (CDCl₃) 7.33-7.26 (m, 1H), 7.00-6.91 (m, 3H), 4.96(s, 1H), 4.62 (bs, 1H), 3.23 (dd, J=14, 5.3, 2H), 1.44 (s, 9H); AnalCalcd for C₁₄H₁₈NO₄F: C, 59.36; H, 6.40; N, 4.94. Found: C, 59.29; H,6.34; N, 4.90.

L-[2-(3-Fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamicacid-tert-butyl ester.

To a solution ofL-2-tert-butoxycarbonylamino-3-(3-fluoro-phenyl)-propionic acid (30.9 g,109 mmol) in THF (180 mL) was added carbonyldiimidazole (21.2 g, 131mmol, 1.2 eq). After stirring the solution at ambient temperature for 45min was added DMF (64 mL), N,O-dimethylhydroxylamine hydrochloride (11.7g, 120 mmol, 1.1 eq) and diisopropylethylamine (20 mL, 113 mmol, 1.04eq). After stirring for a total time of 2 h, the solvents wereevaporated in vacuo and the oily residue dissolved in EtOAc (300 mL).The organic phase was washed with H₂O (500 mL), 10% citric acid (2×150mL), H₂O (500 mL), sat'd Na₂CO₃ (200 mL), brine (200 mL), dried (Na₂SO₄)and concentrated to give the product suitable for further use (31.6 g,89%). ¹H NMR (CDCl₃) 7.29-7.22 (m, 1H), 6.98-6.89 (m, 3H), 5.20 (bs,1H), 4.96 (bs, 1H), 3.72 (s, 3H), 3.19 (s, 3H), 3.07 (dd, J=13.6 ,5.9,2H), 1.41 (s, 9H). Anal Calcd for C₁₆H₂₃N₂O₄F: C, 58.88; H, 7.10; N,8.58. Found: C, 58.89; H, 7.19; N, 8.71.

L-[1-(3-Fluoro-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester.

To a 3-neck flask which purged with argon was added a 1M solution of LAHin Et₂O (106 mL, 1.1 eq) and cooled to 0° C. A solution ofL-[2-(3-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamicacid-tert-butyl ester (3 1.6 g, 97 mmol, 1 eq) in THF (150 mL) was addedover a period of 1 h such that the temperature remained below 5 C. Afterstirring for an additional 30 min the reaction was quenched with EtOAc(60 mL) followed by 5% KHSO₄ (100 mL). EtOAc (500 mL) was added and theorganic phase was washed with 1N HCl (3×100 mL), H₂O (500 mL), brine(200 mL), dried (Na₂SO₄) and concentrated to a white solid which wasfiltered and washed with heptane (200 mL). The aldehyde was suitable forfurther use (17.6 g, 68%). ¹H NMR (CDCl₃) 9.65 (s, 1H), 7.33-7.26 (m,1H), 7.01-6.89 (m, 3H), 5.06 (bs, 1H), 4.43 (broad m, 2H), 1.45 (s, 9H).Anal Calcd for C₁₄H₁₈NO₃F: C, 62.91; H, 6.79; N, 5.24. Found: C, 62.73;H, 6.66; N, 5.21.

3-tert-Butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyric acid(diastereomeric).

A solution of L-[1-(3-fluoro-benzyl)-2-oxo-ethyl]-carbamic acidtert-butyl ester (17.6 g, 66 mmol, 1 eq) in MeOH (104 mL) was cooled to0° C. A solution of sodium bisulfite in H₂O (104 mL) was added and themixture stirred for 5 h at 0° C. after which it was placed in a freezerfor 7 h. The reaction mixture was then charged with a solution of NaCN(3.87 g, 79 mmol, 1.2 eq) in H₂O (104 mL) followed by EtOAc (280 mL) andstirred at room temperature for 11 h after which the organic layer wasseparated, dried (Na₂SO) and concentrated to give the crude cyanohydrinas a waxy solid. This material was dissolved in 1,4 dioxane (265 mL),charged with anisole (11 mL) and cooled to 0° C. Concentrated HCl (265mL) was added, with vigorous stirring, to the reaction mixture followedby heating at reflux for 1 h. The dioxane plus most of the water wasevaporated in vacuo. The remaining residue was basified with 2N NaOH andwashed with Et₂O (3×200 mL). The aqueous phase was then charged with 1,4dioxane (120 mL) followed by BOC₂O (15.8 g, 1.1 eq). After stirring atambient temperature for 3 h the dioxane was removed in vacuo and theremaining mixture acidified with 10% citric acid followed by extractionwith EtOAc (2×300 ml). The combined organic layers were washed with H₂O(300 mL), brine (200 mL), dried (Na₂SO₄) and concentrated to give theacid as diastereomeric mixture (ca 1:1) and orange solid (10.56 g, 51%)¹H NMR (DMSO) 7.35-7.25 (m, 2H), 7.06-6.96 (m, 6H), 6.76 (d, J=9.0, 1H),6.43 (d, J=9.6, 1H), 4.02-3.89 (m, 4H), 3.57 (m, 2H), 2.83 (dd, J=13.4,6.1, 2H), 1.28 (s, 9H), 1.26 (s, 9H).

(2S,3R)-3-tert-Butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyricacid methyl ester.

To a solution of3-tert-butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyric acid(diastereomeric) (10.56 g, 33.8 mmol., 1 eq) in DMF (130 mL) wassuspended K₂CO₃ (6.07 g, 43 mmol, 1.3 eq) followed by CH₃I (4.2 mL, 68mmol, 2 eq). After stirring for 2 h at ambient temperature the DMF wasevaporated in vacuo. The remaining residue was dissolved in EtOAc (300mL) and washed with H₂O (2×100 mL), sodium thiosulfate solution (100mL), brine (200 mL) dried (Na₂SO₄) and concentrated to give a crudeorange solid (9.55 g). Purification by column chromatography (1:1EtOAc/hexanes) afforded 6.96 g total (63%); of which 3.28 g being thedesired diastereomer(2S,3R)-3-tert-Butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyricacid methyl ester (cream colored solid), and 3.68 g being the undesiredproduct(2R,3R)-3-tert-butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyricacid methyl ester. (2S,3R) product: ¹H NMR (CDCl₃) 7.30-7.22 (m, 1H),7.01-6.90 (m, 3H), 4.88 (d, J=8.2, 1H), 4.32 (m, 2H), 3.67 (s, 3H), 2.79(t, J=6.9, 2H), 1.40 (s, 9H). (2R,3R) product: ¹H NMR (CDCl₃) 7.32-7.25(m, 1H), 7.09-6.91 (m, 3H), 4.82 (d, J=9.8, 1H), 4.27 (dd, J=16.9, 7.6,1H), 4.08 (d, J=3.2, 1H), 3.78 (s, 3H), 3.17 (d, J=4.5, 1H), 2.93 (d,J=4.5, 1H), 1.40 (s, 9H).

(2S,3R)-3-tert-Butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyricacid.

A mixture of(2S,3R)-3-tert-Butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyricacid methyl ester (3.28 g, 10.05 mmol, 1 eq), 4N NaOH (4 mL, 16 mmol,1.6 eq), MeOH (42 mL) and 1,4-dioxane (63 mL) was stirred at ambienttemperature for 1.5 h after which the solvents were evaporated. To theresidue was added 10% citric acid (100 mL) followed by extraction withEtOAc (100 mL). The organic layer was washed with H₂O (100 mL), brine(50 mL), dried (Na₂SO₄) and concentrated to give the desired product asa cream colored solid (3.06 g, 97%). ¹H NMR (DMSO) 7.33-7.26 (m, 1H),7.02-6.97 (m, 3H), 6.78 (d, J=5.2, 1H), 3.98 (d, J=5.5, 1H), 3.99-3.86(m, 2H), 2.77-2.82 (m, 2H), 1.27 (s, 9H).

Conversion of undesired (2R,3R) diastereomer-methylester to(2S,3R)-3-tert-butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyricacid.

(2S,3R)-3-tert-Butoxycarbonylamino-2-(2-chloro-acetoxy)-4-(3-fluoro-phenyl)-butyricacid methyl ester.

A solution of the(2R,3R)-3-tert-butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyricacid methyl ester (8 g, 24.5 mmol, 1 eq), chloroacetic acid (5.79 g,61.3 mmol, 2.5 eq), and PPh₃ (16 g, 61.3 mmol, 2.5 eq) in benzene (340mL) was cooled to 0° C. followed by the addition ofdiethylazodicarboxylate (9.7 mL, 61.3 mmol, 2.5 eq) over a 20 minperiod. After the addition, the reaction mixture was stirred at ambienttemperature for 2 h after which the reaction mixture was concentratedand the residue purified by column chromatography with 30% EtOAc/hexanesas eluant. Appropriate fractions were combined and concentrated to givea yellow solid which was shaken with heptane and filtered to remove theyellow DEAD residues. The product was thus obtained as a white solid(4.25 g, 43%) ¹H NMR (CDCl₃) 7.32 (m, 1H), 7.03-6.96 (m, 3H), 5.34 (d,J=3.5, 1H), 4.26 (s, 2H), 4.75-4.5 (series of m, 2H), 3.77 (s, 3H), 2.92(bd, J=7, 2H), 1.43 (s, 9H).

(2S,3R)-3-tert-butoxycarbonylamino-4-(3-fluoro-phenyl)-2-hydroxy-butyricacid.

A mixture of(2S,3R)-3-tert-butoxycarbonylamino-2-(2-chloro-acetoxy)-4-(3-fluoro-phenyl)-butyricacid methyl ester (4.56 g, 11.3 mmol, 1 eq), 4N NaOH (6.5 mL, 25.9 mmol,2.3 eq), MeOH (48 mL) and 1,4-dioxane (72 mL) was stirred at ambienttemperature for 4 h after which the solvents were removed in vacuo andthe residue was charged with H₂O (50 mL) and washed with Et₂O (100 mL).The aqueous layer was made acidic with 10% citric acid and extractedwith EtOAc (2×75 mL). The combined EtOAc layers were washed with H₂O(3×50 mL) brine (50 mL), dried (Na₂SO₄), concentrated, shaken withheptane and filtered to give the desired acid as a white solid (3.3 g,94%).

¹H NMR (DMSO) 9.42 (s, 1H), 8.26 (d, J=8.1, 1H), 8.17 (t, J=5.9, 1H),7.32 (m, 1H), 7.18 (m, 2H), 7.00 (m, 2H), 6.79 (d, J=8.1, 1H), 6.56 (d,J=7.5, 1H), 5.79 (m, 1H), 5.51 (d, J=6.4, 1H), 5.24 (d, J=15.4, 1H),5.06 (d, J=10.4, 1H), 4.49-4.28 (series of m, 5H), 3.74 (broad m, 2H),2.89-2.67 (m, 2H), 1.81 (s, 3H), 1.22 (s, 3H), 1.05 (s, 3H). Anal Calcdfor C₂₈H₃₂N₃O₅F₃x0.25H₂O: C, 60.91; H, 5.93; N, 7.61. Found: C, 60.96;H, 6.05; N, 7.20.

EXAMPLE D3(S)-4,4-Difluoro-1-[(2S,3S)-4-(3-fluoro-phenyl)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid isobutyl-amide

White solid: ¹H NMR (DMSO-d₆) □ 9.14 (s, 1H), 8.03 (d, 1H, J=8.3), 7.76(t, 1H, J=5.8), 7.09 (dd, 1H, J=7.4, 14.4), 6.99 (d, 2H, J=7.6),6.81-6.73 (m, 2H), 6.58 (d, 1H, J=8.1), 6.34 (d, 1H, J=6.8), 5.23 (d,1H, J=6.6), 4.25 (dd, 1H, J=12.2, 25.0), 4.15-4.08 (m, 3H), 2.77-2.46(m, 4H), 1.59 (s, 3H), 1.52-1.43 (m, 1H), 1.00 (s, 3H), 0.83 (s, 3H),0.65 (d, 6H, J=6.4); HRMS (ESI) m/z calcd for C₃₀H₃₇F₃N₃O₅ (M+H)⁺564.6130, found: 564.2674; Anal. Calcd for C₃₀H₃₆F₃N₃O₅: C, 61.80; H,6.44; N, 7.46. Found: C, 61.58; H, 6.45; N, 7.34.

EXAMPLE D4(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid propylamide

White solid: ¹H NMR (DMSO-d₆) □ 9.17 (s, 1H), 8.04 (d, 1H, J=8.1), 7.85(t, 1H, J=5.1), 7.29-7.09 (m, 5H), 6.53 (s, 1H), 6.30 (s, 1H), 5.38 (d,1H, J=6.1), 4.40-4.24 (m, 3H), 4.14 (s, 1H), 3.04-2.90 (m, 2H), 2.77 (d,1H, J=2.2), 2.65-2.59 (m, 1H), 2.09 (s, 3H), 1.67 (s, 3H), 1.39-1.31 (m,2H), 1.13 (s, 3H), 0.97 (s, 3H), 0.78 (s, 3H). HRMS (ESI) m/z calcd forC₂₉H₃₈F₂N₃O₅ (M+H)⁺ 546.6230, found 546.2780; Anal. Calcd forC₂₉H₃₇F₂N₃O₅: C, 63.84; H, 6.84; N, 7.70. Found: C, 63.44; H, 6.82; N,7.52.

EXAMPLE D5(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid isobutyl-amide

White solid: ¹H NMR (DMSO-d₆) □ 9.24 (s, 1H), 8.11 (d, 1H, J=8.3), 7.94(t, 1H, J=5.8), 7.37-7.16 (m, 5H), 6.60 (s, 1H), 6.38 (s, 1H), 5.44 (d,1H, J=6.3), 4.48-4.29 (m, 3H), 4.25 (s, 1H), 2.94-2.83 (m, 3H),2.73-2.64 (m, 1H), 2.16 (s, 3H), 1.75 (s, 3H), 1.74-1.65 (m, 1H), 1.21(s, 3H), 1.05 (s, 3H), 0.86 (d, 6H, J=6.6); HRMS (ESI) m/z calcd forC₃₀H₄₀F₂N₃O₅ (M+H)⁺ 560.6500, found: 560.2928; Anal. Calcd forC₃₀H₃₉F₂N₃O₅: C, 64.38; H, 7.02; N, 7.51. Found: C, 64.09; H, 7.05; N,7.29.

EXAMPLE D6(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid (2,2,2-trifluoro-ethyl)-amide

(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid (2,2,2-trifluoro-ethyl)-amide White solid: ¹H NMR (DMSO-d₆) □ 9.27(s, 1H), 8.72 (t, 1H, J=6.2), 8.15 (d, 1H, J=8.1), 7.37-7.19 (m, 5H),6.63 (s, 1H), 6.39 (s, 1H), 5.57 (d, 1H, J=6.3), 4.52-4.33 (m, 4H),4.10-3.94 (m, 1H), 3.93-3.88 (m, 1H), 2.87 (d, 1H, J=7.3), 2.75-2.69 (m,1H), 2.19 (s, 3H), 1.77 (s, 3H), 1.25 (s, 3H), 1.06 (s, 3H); HRMS (ESI)m/z calcd for C₂₈H₃₃F₃N₃O₅ (M+H)⁺ 586.5670, found 586.2340; Anal. Calcdfor° C.₂₈H₃₂F₃N₃O₅.0.4H₂O: C, 56.73; H, 5.58; N, 7.09. Found: C, 56.64;H, 5.41; N, 6.94.

Combinatorial Chemistry Approach to HIV Protease P2′ Inhibitors

General Method E

The combinatorial building block, 8, is prepared using the followingmethod. The boc-protected thiazolidine carboxylic acid, 1, is treatedwith allyl bromide in the presence of NaHCO₃ to yield the boc-protectedthiazolidine allyl ester, 2. Deprotection of boc-protected allyl ester,2, with HCl (g) in EtOAc gives the HCl salt of the thiazolidine allylester amine, 3, which is treated with TEA and coupled to 4 in thepresence of HOBT and DCC to give the building block precursor, 5.Deprotection of the building block, 5, with 4N HCl yields the phenol, 6.Loading the building block, 6, on to activated cross-linked tritylchloride polystyrene beads, 7, was accomplished in the following manner.The polystyrene cross-linked trityl alcohol was activated to the tritylchloride, 7, by treatment with 20% acetyl chloride in anhydrous CH₂Cl₂at room temperature. The trityl chloride beads were combined with thephenol 6 in the presence of Hunig's base in anhydrous CH₂Cl₂ to yieldthe substrate loaded polystyrene beads 8. Intermediates were purifiedeither by flash chromatography or preparative HPLC.

The synthesis of the HIV protease combinatorial library was carried outin the following fashion. The allyl ester was removed by treatment withPd[PPh₃]₄ and NMM in anhydrous THF to give carboxylate 9, which wastreated with pentafluorophenol, pentafluorophenol trifluoromethylacetate and pyridine in DMF to yield the pentafluoro ester, 10. Thepentafluoro ester 10 was treated with various primary amines in a96-well plate format to give amides 12. The final products were cleavedfrom the polystyrene crowns with TFA to give products 13. Each productwas analyzed by LCMS and HPLC. The following table typifies compoundssynthesized by this combinatorial method. TABLE 1 Expected Mass Observed% P2′ (LCMS) Mass Inhibition

582 583 (MH⁺) 5

582 583 (MH⁺) 5

529 552 (Na⁺) 38

528 529 (MH⁺) 4

591 614 (Na⁺) 18

555 578 (Na⁺) 19

611 612 (MH⁺) 1

593 594 (MH⁺) 6

576 577 (MH⁺) 6

635 658 (Na⁺) 5

656 656 (MH⁺) 8

575 598 (Na⁺) 86

525 548 (Na⁺) 56

541 564 (Na⁺) 63

529 552 (Na⁺) 49

565 588 (Na⁺) 42

587 610 (Na⁺) 54

The solid phase combinatorial synthesis of HIV protease inhibitors wasperformed using the IRORI Directed Sorting Technology. Commercial4-formyl-3-methoxyphenoxymethyl polystyrene resin 1a (PS-MB-CHO,Argonaut Technologies) or 4-formyl-3,5-dimethoxyphenoxymethylpolystyrene resin 1b (PL-FDMP resin, Polymer Laboratories) was loadedinto individual MiniKans.

Step A. Reductive Amination with P₂′ Amines

To separate flasks containing sorted MiniKans was added DCM (3mL/MiniKan). The appropriate primary P₂′ amine (3 eq), sodiumtriacetoxyborohydride (5 eq), and acetic acid (3 eq) were added, and themixtures were placed under argon, agitated with periodic venting at roomtemperature for 1-2 hours, and allowed to react overnight. For resin 1a,the filtrates were poured off and the MiniKans were washed with DCM,MeOH (2×), DCM (2×), Et₃N/DCM (1:3, 3×), DCM (2×), MeOH (3×), and DCM(4×). For resin 1b, a washing sequence of DCM, MeOH (2×), DCM (2×),Et₃N/DCM (1:3, 3×), DCM (2×), DMF, 1M NaOH/DMF (1:5, 3×), DMF (3×), MeOH(3×), and DCM (3×) was used. The MiniKans were dried under vacuum andtaken on in Step B.

Step B. Peptide Coupling with P₁′ Amino Acids

To separate flasks containing the sorted MiniKans was added DMF (3mL/MiniKan). The appropriate FMOC-protected amino acid (2.5 eq) and1-hydroxy-7-azabenzotriazole (HOAT) (3 eq) were added and mixed untildissolved, and 1,3-diisopropylcarbodiimide (DIC) (3 eq) was added. Thecontainers were placed under argon and agitated at room temperatureovernight. The filtrates were poured off, and the MiniKans were washedwith DMF (3×), MeOH (3×), DCM (2×), and DMF (2×). The MiniKans weretaken directly on to Step C.

Step C. FMOC Deprotection

A container of MiniKans in DMF and piperidine (25%) with a totalreaction volume of 3 mL/MiniKan was agitated under argon at roomtemperature for 45 minutes. The filtrate was removed, and the reactionprocedure was repeated. The MiniKans were filtered and washed with DMF(3×), MeOH (2×), DCM (3×), and DMF, and taken directly on to Step D.

Step D. Peptide Coupling with FMOC-APNS

FMOC-Allophenylnorstatine (APNS) (3 eq) was added to the flask ofMiniKans in DMF (3 mL/MiniKan). After dissolution, HOAT (3.5 eq) and DIC(3.5 eq) were added. The mixture was placed under argon and agitated atroom temperature overnight. The reaction was filtered and the MiniKanswere washed with DMF (3×), MeOH (3×), DCM (3×), and DMF. FMOCdeprotection was carried out as in Step C, and the MiniKans were washedwith DMF (3×), MeOH (2×), DCM (3×), dried under vacuum and taken on toStep E or F.

Step E. Peptide Coupling with P₂ Acids

To separate flasks containing the sorted MiniKans in DMF (3 mL/MiniKan)was added the appropriate P₂ acid (3 eq), HOBT hydrate (4 eq), and(3-(dimethylamino)propyl)ethylcarbodiimide hydrochloride (EDAC) (3.5eq). The reaction was agitated under argon at room temperature for 3hours. After filtration, the MiniKans were washed with DMF (3×), MeOH(3×), and DCM (3×), dried under vacuum, and taken on to Step G.

Step F. Reaction with P₂ Isocyanates and Chloroformates

To separate flasks containing the sorted MiniKans in DCM (3 mL/MiniKan)was added the P₂ isocyanate (3 eq) or P₂ chlorofornate (5 eq) anddiisopropylethylamine (10 eq). The containers were agitated under argonat room temperature for 2-4 hours. After filtration, the MiniKans werewashed with DCM (3×), MeOH (3×), and DCM (3×), dried under vacuum, andtaken on to Step G.

Step G. Cleavage and Processing of the HIV Analogs

The individual MiniKans were sorted into cleavage racks and a solutionof 25% TFA in DCM (3 mL/MiniKan) was added. The racks were agitated for1.5 hours. The individual filtrates and DCM rinses were collected,concentrated, and purified by HPLC to provide the final compounds. TABLE2

Scheme 3 Experimental

The solid phase combinatorial synthesis of HIV protease inhibitors wasperformed using the IRORI Directed Sorting Technology. Commercial4-formyl-3-methoxyphenoxymethyl polystyrene resin 1a (PS-MB-CHO,Argonaut Technologies) or 4-formyl-3,5-dimethoxyphenoxymethylpolystyrene resin 1b (PL-FDMP resin, Polymer Laboratories) was loadedinto individual MiniKans.

Step A. Reductive Amination with P₂′ Amines

To separate flasks containing sorted MiniKans was added DCM (3mL/MiniKan). The appropriate primary P₂′ amine (3 eq), sodiumtriacetoxyborohydride (5 eq), and acetic acid (3 eq) were added, and themixtures were placed under argon, agitated with periodic venting at roomtemperature for 1-2 hours, and allowed to react overnight. For resin 1a,the filtrates were poured off and the MiniKans were washed with DCM,MeOH (2×), DCM (2×), Et₃N/DCM (1:3, 3×), DCM (2×), MeOH (3×), and DCM(4×). For resin 1b, a washing sequence of DCM, MeOH (2×), DCM (2×),Et₃N/DCM (1:3, 3×), DCM (2×), DMF, 1M NaOH/DMF (1:5, 3×), DMF (3×), MeOH(3×), and DCM (3×) was used. The MiniKans were dried under vacuum andtaken on in Step B.

Step B. Peptide Coupling with P₁′ Amino Acids

To separate flasks containing the sorted MiniKans was added DMF (3mL/MiniKan). The appropriate FMOC-protected amino acid (2.5 eq) and1-hydroxy-7-azabenzotriazole (HOAT) (3 eq) were added and mixed untildissolved, and 1,3-diisopropylcarbodiimide (DIC) (3 eq) was added. Thecontainers were placed under argon and agitated at room temperatureovernight. The filtrates were poured off, and the MiniKans were washedwith DMF (3×), MeOH (3×), DCM (2×), and DMF (2×). The MiniKans weretaken directly on to Step C.

Step C. FMOC Deprotection

A container of MiniKans in DMF and piperidine (25%) with a totalreaction volume of 3 mL/MiniKan was agitated under argon at roomtemperature for 45 minutes. The filtrate was removed, and the reactionprocedure was repeated. The MiniKans were filtered and washed with DMF(3×), MeOH (2×), DCM (3×), and DMF, and taken directly on to Step D.

Step D. Peptide Coupling with FMOC-APNS

FMOC-Allophenylnorstatine (APNS) (3 eq) was added to the flask ofMiniKans in DMF (3 mL/MiniKan). After dissolution, HOAT (3.5 eq) and DIC(3.5 eq) were added. The mixture was placed under argon and agitated atroom temperature overnight. The reaction was filtered and the MiniKanswere washed with DMF (3×), MeOH (3×), DCM (3×), and DMF. FMOCdeprotection was carried out as in Step C, and the MiniKans were washedwith DMF (3×), MeOH (2×), DCM (3×), dried under vacuum and taken on toStep E or F.

Step E. Peptide Coupling with P₂ Acids

To separate flasks containing the sorted MiniKans in DMF (3 mL/MiniKan)was added the appropriate P₂ acid (3 eq), HOBT hydrate (4 eq), and(3-(dimethylamino)propyl)ethylcarbodiimide hydrochloride (EDAC) (3.5eq). The reaction was agitated under argon at room temperature for 3hours. After filtration, the MiniKans were washed with DMF (3×), MeOH(3×), and DCM (3×), dried under vacuum, and taken on to Step G.

Step F. Reaction with P₂ Isocyanates and Chloroformates

To separate flasks containing the sorted MiniKans in DCM (3 mL/MiniKan)was added the P₂ isocyanate (3 eq) or P₂ chloroformate (5 eq) anddiisopropylethylamine (10 eq). The containers were agitated under argonat room temperature for 24 hours. After filtration, the MiniKans werewashed with DCM (3×), MeOH (3×), and DCM (3×), dried under vacuum, andtaken on to Step G.

Step G. Cleavage and Processing of the HIV Analogs

The individual MiniKans were sorted into cleavage racks and a solutionof 25% TFA in DCM (3 mL/MiniKan) was added. The racks were agitated for1.5 hours. The individual filtrates and DCM rinses were collected,concentrated, and purified by HPLC to provide the final compounds. TABLE3

Biological Evaluation

Cells and Virus

T-cell lines, CEM-SS, and MT-2, and viruses HIV-1 RF and HIV-1 NL4-3(pNL4-3) were obtained from the National Institutes of Health (AIDSResearch and Reference Reagent Program, Bethesda, MD). HIV-1 NL4-3(184V/L90M) was derived from a clinical isolate that exhibited theprotease inhibitor-resistance associated substitutions 184V and L90M, bycloning of an reverse transcriptase-polymerase chain reaction amplifiedfragment into the unique AgeI and SpeI restriction sites of pNL4-3.

Cytopathic Effect (CPE) Inhibition Assays

The ability of compounds to protect cells against HIV infection wasmeasured by the MTT dye reduction method, essentially as described (SeePauwels, R. Balzarini, J. Baba, M. Snoeck, R. Schols, D. Herdewijn, P.Desmyter, J. and De Clercq, E. 1988, “Rapid and automatedtetrazolium-based calorimetric assay for the detection of anti-HIVcompounds,”. J Virol. Methods., 20: 309-321 and Weislow, O. S. Kiser, R.Fine, D. L. Bader, J. Shoemaker, R. H. and Boyd, M. R. 1989. “Newsoluble-formazan assay for HIV-1 cytopathic effects: application tohigh-flux screening of synthetic and natural products for AIDS-antiviralactivity”. J. Natl. Cancer Inst. 81:577-586). Subject cells wereinfected with test virus at an moi of 0.025 to 0.819 or mock infectedwith medium only and added at 2×10⁴ cells per well into 96 well platescontaining half-log dilutions of test compounds. Six days later, 50 μlof XTT (1 mg/ml XTT tetrazolium, 0.02 nM phenazine methosulfate) wasadded to the wells and the plate was reincubated for four hours.Viability, as determined by the amount of XTT formazan produced, wasquantified spectrophotometrically by absorbance at 450 nm. Data from CPEassays were expressed as the percent of formazan produced incompound-treated cells compared to formazan produced in wells ofuninfected, compound-free cells. The fifty percent effectiveconcentration (EC₅₀) was calculated as the concentration of compoundthat effected an increase in the percentage of formazan production ininfected, compound-treated cells to 50% of that produced by uninfected,compound-free cells. The 50% cytotoxicity concentration (CC₅₀) wascalculated as the concentration of compound that decreased thepercentage of formazan produced in uninfected, compound-treated cells to50% of that produced in uninfected, compound-free cells. The therapeuticindex was calculated by dividing the cytotoxicity (CC₅₀) by theantiviral activity (EC₅₀).

Susceptibility Assays

Compounds were tested in phenotypic susceptibility assays at Virologic,Inc., (See Petropoulos C. J., Parkin N. T., Limoli K. L., Lie Y. S.,Wrin T., Huang W., Tian H., Smith D., Winslow G. A., Capon D J, WhitcombJ M. 2000, “A novel phenotypic drug susceptibility assay for humanimmunodeficiency virus type 1,” Antimicrob Agents Chemother44(4):920-928) or using the assay described here. MT-2 cells wereinfected with either HIV-1 NL4-3 or HIV-1 NL4-3(184V/L90M) and incubatedin the presence of serial 0.5 log dilutions of test compounds. Threedays later, culture supernatants were collected and virus production, asdetermined by p24 ELISA, was assayed. Percent inhibition was calculatedas p24 concentration in compound-treated samples as compared toinfected, compound-free controls. Inhibition of viral replication isdetermined by measuring reduction in HIV p24 present in the culturesupernatant, using a Beckman-Coulter p24 HIV-1 Ag EIA kit and followingthe supplied protocol. Absorbance is read on a MRX microplate reader(Dynex Technologies). The EC₅₀ was calculated as the concentration ofcompound that effected a decrease in the p24 production by infected,compound-treated cells to 50% of that produced by infected,compound-free cells.

HIV-1 Protease RET Assay

Ki's for the inhibitors of HIV-1 protease were determined using aresonance energy transfer (RET) assay. A mutant form of this enzyme(Q7S) is used for this assay because it is more stable againstauto-proteolysis than the wild-type protein. This enzyme is firstpartially purified as inclusion bodies from cell lysate. It is thensolublized in 8M urea and passed through a Q-Sepharose column(Pharmacia) for further purification. To refold this protein, samplescontaining Q7S is dialyzed into 50 mM sodium phosphate pH 7.0, 50 mMNaCl, 10 mM DTT, and 10% glycerol.

The commercially available peptide substrate (Molecular Probes Cat.#H-2930) RE(EDANS)SQNYPIVQK(DABCYL)R is used to assess activity andKi's. This peptide is cleaved quantitatively by HIV-1 Pr at the Tyr-Probond. The EDANS fluorophore absorbs at 340 mm and emits at 490 nm. Thereaction is carried out in a 96 well plate in a total volume of 100 μLand is run for 12 minutes at 37 C under steady-state conditions with 5μM substrate and 2 nM active dimer enzyme concentration. The literaturevalue Km for this substrate and enzyme is 103 +/−8 μM (See Matayoshi, etal., “Novel Fluorogenic Substrates for Assaying Retroviral Proteases byResonance Energy Transfer,” Science 247, 954 (1990)). The buffer forthis reaction is 0.1M sodium acetate pH 4.8, 1M NaCl, 1 mM EDTA, 5 mMdithiothreitol, 10% dimethyl sulfoxide and 1 mg/ml bovine serum 5albumin. Inhibition curves are fit using the Morrison tight bindingequation. Ave CPE EC₅₀ or Example No. Ave. K_(i) (nM) EC₅₀ (mM) IC₅₀(mM) A1 0.21 0.029 A3 0.51 0.156 A4 2.2 0.27 A5 0.2 0.148 A6 0.23 0.036A7 1.7 0.113 A8 1.4 0.451 A9 0.49 0.138 1.081 A10 <0.1 0.104 0.118* A110.5 0.144 A12 5.5 0.127 A13 3.4 0.495 0.921* A14 0.32 0.061 0.226* A15<0.1 0.055 0.057* A16 0.43 0.254 A17 <0.1 0.024 0.049* A18 0.3 0.027 A190.21 0.015 A20 0.16 0.035 0.219* A21 <0.1 0.049 0.655* A22 <0.1 0.1380.318 A23 2.6 0.017 0.048* A24 0.52 0.466 A25 0.97 0.125 A26 0.6 0.168A27 <0.1 0.11 A28 3.4 0.327 A29 0.31 0.118 A30 10.9 0.586 A31 0.44 0.062A32 <0.1 0.012 0.055* A33 5.1 0.749 A34 1.4 0.386 A35 <0.1 0.016 0.041*A36 0.78 0.343 A37 3.7 0.416 A38 <0.1 0.038 A39 <0.1 0.123 0.213 A40<0.1 0.04 0.109 A41 0.17 0.145 0.242 A42 <0.1 0.065 0.098 A43 2.6 0.534A44 1.4 0.478 A45 <0.1 0.034 0.048 A46 1.1 0.469 A47 0.27 0.196 A48 <0.10.037 0.092 A49 0.49 0.161 A50 <0.1 0.024 0.125 A51 <0.1 0.159 0.05 A520.51 0.456 A53 <0.1 0.028 0.07 A54 4.5 1.231 A55 0.21 0.054 0.798 A560.27 0.042 0.378 A57 5.6 1.531 A58 13% @ 64 nM A59 0.19 0.417 A60 66.6A61 0.99 1.061 A62 9.6 2.261 A63 4.5 1.189 A65  0% @ 64 nM B1 0.27 0.0490.236* B2 0.35 0.087 B3 2.5 0.905 B4 3 0.707 B5 1.2 0.314 B6 0.31 0.0950.405* B7 <0.1 0.265 0.333* B8 0.63 0.474 B9 1.1 0.452 B10 0.57 0.386B11 0.86 0.567 2.015 B12 9.9 >1 B13 2 1.458 B14 2.7 1.661 B15 1.3 2.305B16 2.6 1.566 B17 4.8 B18 0.56 1.25 B19 1.4 1.595 1.298 B20 2.1 1.5632.084* B21 0.91 0.109 0.547* B22 12 0.246 B23 0.15 0.294 B24 8.3 0.512B25 21 >1 B26 2.1 0.348 B27 0.5 0.506 B28 4.2 0.731 B29 0.82 0.063 B300.21 0.443 B31 4.7 >1 B32 0.48 0.433 B33 <0.1 0.045 0.604* B34 1.2 0.389B35 11 0.564 B36 <0.1 0.519 B37 7.4 0.529 B38 0.16 0.6 B39 1.9 0.372 B4015.1 >1 B41 0.11 0.268 B42 0.13 0.155 B43 <0.1 0.375 B44 4.8 0.66 B451.1 0.572 B46 93 B47 1.9 1.477 B48 0.83 1.478 B49 120 B50 7.4 B510.99 >3.2 B52 120 B54 2.3 1.659 B55 679 B56 153 B57 16% @ 64 nM B58 240B59 2.1 1.815 B60 1.1 >3.2 B61 16.9 B62 4.2 B63 7.8 B64 0.53 1.603 B654.9 1.636 B66 5.2 B67 11.4 >3.2 B68 36 B69 7.7 B70 21 B71 6.4 B72 6.6B73 13 B74 39 B75 81 B76 11.2 B77 <0.1 0.143 1.633 B78 0.18 0.557 B790.78 0.53 B80 0.15 0.419 1.383 B81 0.35 0.878 B82 0.19 1.286 B83 <0.10.009 0.202 B84 <0.1 0.009 0.686 B85 1.3 0.363 C1 0.38 0.627 0.427 C30.16 0.486 C4 0.17 0.236 1.903 C5 0.6 0.669 1.608 C6 2.4 0.744 1.944 C73 0.347 C8 1.5 0.152 1.419 C9 6.3 C10 1.5 1.289 C11 2.8 1.308 C12 2.71.768 C13 0.59 1.184 C14 2.5 C15 <0.1 0.025 0.057 C16 <0.1 0.019 0.201C17 <0.1 0.115 0.186 C18 <0.1 0.148 0.618 C19 <0.1 0.055 0.084 C20 <0.10.035 C21 <0.1 0.015 0.081 C22 <0.1 0.015 0.062 C23 <0.1 0.037 0.109 C24<0.1 0.019 0.074 C25 <0.1 0.031 0.068 C26 <0.1 0.076 0.131 C27 0.130.115 0.189 C28 8.4 C29 0.18 0.142 1.359 C30 <0.1 0.018 0.273 C31 0.170.031 1.067 C32 <0.1 0.009 0.19 C33 0.13 0.045 1.27 C34 <0.1 0.022 0.627C35 <0.1 0.003 0.289 C36 <0.1 0.05 0.666 C37 0.61 0.027 1.293 C38 <0.10.042 1.313 C39 <0.1 0.013 0.404 C40 1.8 1.599 C40 0.82 0.174 1.796 C411.3 1.433 C42 4 3.2 C43 21 C44 14.8 C45 3.6 1.575 C46 <0.1 0.407 C47 1.41.382 C48 <0.1 0.128 C49 150 C50 7.9 0.997 D1 <0.1 0.052 0.601 D2 <0.10.016 D3 <.01 0.013 D4 <0.1 0.009 D5 <0.1 0.011 D6 <0.1 0.018*IC₅₀ (mM) Data was determined at Virologic Inc against the 46I, 84V,90M virus

The following compounds have been prepared according to the proceduresdescribed herein and have demonstrated the noted activity: MOLSTRUCTUREK_(i) EC₅₀

0.1 0.014

10

0.34 0.04

4.22

468

152

6.8

0.1 0.126

14.2

20

74

7.6

0.1 0.027

10

0.1 0.041

148

368

30

13.9

21

21

54

25

17

0.39 0.332

125

6.1

0.76 0.573

68

8.1

0.25 0.879

6.4 0.901

4.7 1

7.8

2 0.488

59

3.8

109 0.672

47

5

11.9

0.78 1

3.4

4.2 1

4.4

8.2

0.13 1.16

.9 1.176

27

2.3 1.215

47

3.9 1.232

18.1

6.7 1.008

6

0.38 1.109

5.4

4.3 1.188

92

29

26 1.23

99

7.5 1.252

6.1 1.281

3 1.293

4.7

17.2 1.328

4.8 1.35

117

59

0.44 1.431

0.1 1.536

6.9 1.551

1.1 1.552

45

108

122

7.6

72

11.5

20

6.2

83

11

42

108

3.7 1.553

84

156

0.88 1.641

7.6 1.756

0.32 1.884

1.4 1.947

7.4 1.957

17.1 2.199

88

48

28 3.2

0.89 1.564

51

110

18.7

158

60

85

94

9.4 2.881

9.9

17.4 3.2

52

30

17.3

53

3.2

12.6 3.2

15.1 3.2

12.9

185 3.916

1.4 4.224

46 10

82 3.2

5.8 3.2

4.4 3.2

9.8 3.2

12.7 3.2

8.4 3.2

3.6 3.2

134

18.4 3.995

51.7 5.873

While the invention has been described in terms of preferred embodimentsand specific examples, those skilled in the art will recognize thatvarious changes and modifications can be made through routineexperimentation without departing from the spirit and scope of theinvention. Thus, the invention should be understood as not being limitedby the foregoing detailed description, but as being defined by theappended claims and their equivalents.

1. A compound having the Formula I:

wherein: R¹ is a carbocyclic group; V is C═O, C═S or SO₂; R² is analiphatic group, a carbocyclic group, a carbocyclic-aliphatic group, aheterocyclic group, a heterocyclic-aliphatic group or N(R^(2a))R^(2b),wherein R^(2a) is an aliphatic, carbocyclic or heterocyclic group, andR^(2b) is H or a C₁-C₆ aliphatic group; W is N; R^(2′) is H or a C₁-C₆aliphatic group or R² and R^(2′) taken together with the atom W to whichthey are attached form an unsubstituted or substituted carbocyclic orheterocyclic ring; X is

where R^(x) is H or one or more substituents independently selected fromC₁-C₆ alkyl, nitro, amino, cyano, halogen, C₁-C₆ haloalkyl, hydroxyl,C₁-C₆ alkoxy, alkylenedioxy, C₁-C₆ alkylcarbonyl, C₁-C₆alkyloxycarbonyl, C₁-C₆ alkylcarbonyloxy, carboxyl, carbamoyl, formyl,C₁-C₆ alkylamino, dialkylamino, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminothiocarbonyl,di-C₁-C₆-alkylaminothiocarbonyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylsulfenyl, C₁-C₆ alkylcarbonylamino, C₁-C₆ alkylthiocarbonylamino,C₁-C₆ alkylsulfonyloxy, C₁-C₆ alkylsulfonylamino, mercapto, and C₁-C₆alkylthio; R⁸ and R^(8′) are each independently H, halo or a C₁-C₄aliphatic group; A is CH₂, CH(R^(A)) or is absent; Z is CH₂, CHF, CF₂,CH(OH), CH(O—R^(Z)), CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), orCH(R^(Z)), where R^(Z) is a C₁-C₆ aliphatic group or a carbocyclic orheterocyclic group and R^(Z′) is H or a C₁-C₆ aliphatic group; or R^(A)and R^(Z) , taken together with A and Z form an unsubstituted orsubstituted 5 or 6 membered carbocyclic or heterocyclic ring; R³ is H ora C₁-C₆ aliphatic group; R⁴ and R⁵ are independently selected from H,halo, a C₁-C₆ aliphatic group or a group having the formula C(O)R^(4′),wherein R^(4′) is an aliphatic, carbocyclic or heterocyclic group; or R⁴and R⁵, taken together with the atom to which they are bound, form anunsubstituted or substituted carbocyclic ring; or R⁴ and R⁶ or R⁷,together with the atoms to which they are bound, form an unsubstitutedor substituted carbocyclic ring; R⁶ and R⁷ are independently selectedfrom H, halo or a C₁-C₆ aliphatic group; or R⁶ and R⁷, taken togetherwith the atom to which they are bound, form an unsubstituted orsubstituted carbocyclic or heterocyclic group; wherein any of saidaliphatic groups are saturated, partially saturated or fully unsaturatedand unsubstituted or substituted by one or more suitable substituents;and wherein any of said carbocyclic or heterocyclic groups areunsubstituted or substituted by one or more suitable substituents;saturated, partially unsaturated or fully unsaturated; or mono-, bi- ortri-cyclic; provided that R² is not an aliphatic group, a phenyl groupor a phenyl-substituted aliphatic group, when A is absent, Z is CHF orCH₂, V is C═O; W is N, R², R³, R⁸ and R^(8′) are H or a C₁-C₄ alkylgroup, R⁴, R⁵, R⁶ and R⁷ are H or a C₁-C₆ alkyl group, X is

and R¹ is a substituted or unsubstituted 5 or 6-membered mono-cycliccarbocyclic group; or a prodrug, pharmaceutically acceptable salt, orpharmaceutically acceptable solvate thereof.
 2. A compound having theFormula I-A:

wherein: R¹ is a mono-, bi- or tri-cyclic carbocyclic group; R² is analiphatic group, a carbocyclic group, a carbocyclic-aliphatic group, aheterocyclic group, or a heterocyclic-aliphatic group; R^(2′) is H or aC₁-C₆ alkyl group; or R² and R^(2′) taken together with the nitrogenatom to which they are attached form an unsubstituted or substitutedcarbocyclic or heterocyclic ring; X is

wherein R^(x) is H or one or more substituents independently selectedfrom alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy,alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy,carboxyl, carbamoyl, formyl, alkylamino, dialkylamino,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl,alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy,alkylsulfonylamino, mercapto, and alkylthio; R⁸ and R^(8′) are eachindependently H, halo or a C₁-C₄ aliphatic group; Z is CH₂, CHF, CF₂,CH(OH), CH(O—R^(Z)), CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), orCH(R^(Z)), where R^(Z) is a C₁-C₆ aliphatic group or a carbocyclic orheterocyclic group and R^(Z′) is H or a C₁-C₆ aliphatic group; R³ is Hor a C₁-C₆ aliphatic group; R⁴ and R⁵ are independently selected from H,halo, a C₁-C₆ aliphatic group or a group having the formula C(O)R^(4′),wherein R^(4′) is an aliphatic, carbocyclic or heterocyclic group; R⁶and R⁷ are independently selected from H, halo or a C₁-C₆ aliphaticgroup; wherein any of said aliphatic groups are unsubstituted orsubstituted by one or more suitable substituents and saturated,partially unsaturated or fully unsaturated; and wherein any of saidcarbocyclic or heterocyclic groups are mono-, bi- or tri-cyclicsaturated, partially unsaturated or fully unsaturated or unsubstitutedor substituted by one or more suitable substituents; provided that R² isnot an aliphatic group, a phenyl group or a phenyl-substituted aliphaticgroup, when Z is CHF or CH₂, R², R³, R⁸ and R^(8′) are H or a C₁-C₄alkyl group, R⁴, R⁵, R⁶ and R⁷ are H or a C₁-C₆ alkyl group, X is

and R¹ is a substituted or unsubstituted 5- or 6-membered mono-cycliccarbocyclic group; or a prodrug, pharmaceutically acceptable salt, orpharmaceutically acceptable solvate thereof.
 3. The compound, prodrug,salt, or solvate according to claim 2, wherein: R¹ is a 5- or 6-memberedmonocyclic carbocyclic group; and R² is cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, a bi- or tri-cyclic carbocyclic group,a bi- or tri-cyclic carbocyclic-alkyl group, a bi- or tri-cycliccarbocyclic-alkenyl group, a bi- or tri-cyclic carbocyclic-alkynylgroup, a heterocyclic group, a heterocyclic-alkyl group, aheterocyclic-alkenyl group or a heterocyclic-alkynyl group.
 4. Thecompound, prodrug, salt, or solvate according to claim 2, wherein: R¹ isa bi- or tri-cyclic carbocyclic group, wherein said carbocyclic group issaturated, partially unsaturated or fully unsaturated; and unsaturatedor substituted by one or more suitable substituents.
 5. A compoundhaving the Formula I-A′:

wherein: R¹ is a bi- or tri-cyclic cycloalkyl, cycloalkenyl, or arylgroup; R² is a cycloalkyl, cycloalkylalkyl, cycloalkenyl, orcycloalkenylalkyl group, a bi- or tri-cyclic aryl group, a bi- ortri-cyclic arylalkyl group, a bi- or tri-cyclic arylalkenyl group, a bi-or tri-cyclic arylalkynyl group, or a heterocycloalkyl,heterocycloalkylalkyl, heterocycloalkenyl, heterocycloalkenylalkyl,heteroaryl or heteroarylalkyl group; R^(2′) is H or a C₁-C₆ alkyl group;or R² and R^(2′) taken together with the nitrogen atom to which they areattached form a heterocycloalkyl or heterocycloalkenyl ring; X is

wherein R^(x) is H or one or more substituents independently selectedfrom alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy,alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy,carboxyl, carbamoyl, formyl, alkylamino, dialkylamino,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl,alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy,alkylsulfonylamino, mercapto, and alkylthio; Z is CH₂, CHF, CF₂, CH(OH),CH(O—R^(Z)), CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C(═O), or CH(R^(Z)), whereR^(Z) is a C₁-C₆ aliphatic group or a carbocyclic or heterocyclic groupand R^(Z′) is H or a C₁-C₆ aliphatic group; R³ is H or a C₁-C₆ aliphaticgroup; R⁴ and R⁵ are independently selected from H, halo, and a C₁-C₆aliphatic group; R⁶ and R⁷ are independently selected from H, halo and aC₁-C₆ aliphatic group; where any of the alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl orheteroaryl groups or the alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroarylmoieties of the cycloalkylalkyl, cycloalkenylalkyl, arylalkyl,heterocycloalkylalkyl, heterocycloalkenylalkyl, heteroarylalkyl,cycloalkylalkenyl, cycloalkenylalkenyl, arylalkenyl,heterocycloalkylalkenyl, heterocycloalkenylalkenyl, heteroarylalkenyl,cycloalkylalkynyl, cycloalkenylalkynyl, arylalkynyl,heterocycloalkylalkynyl, heterocycloalkenylalkynyl, andheteroarylalkynyl groups are unsubstituted or substituted by one or moresuitable substituents; and where any of said carbocyclic or heterocyclicgroups are mono-, bi- or tri-cyclic; saturated, partially unsaturated orfully unsaturated, and unsubstituted or substituted by one or moresuitable substituents; provided that R² is not an aliphatic group, aphenyl group or a phenyl-substituted aliphatic group, when Z is CHF orCH₂, R^(2′) and R³ are H or a C₁-C₄ alkyl group, R⁴, R⁵, R⁶ and R⁷ are Hor a C₁-C₆ alkyl group, X is

and R¹ is a substituted or unsubstituted 5 or 6-membered mono-cycliccarbocyclic group; or a prodrug, pharmaceutically acceptable salt, orpharmaceutically acceptable solvate thereof.
 6. The compound, prodrug,salt, or solvate according to claim 7, wherein: Z is CF₂, CH(OH),CH(O—R^(Z)), CH(N—R^(Z)R^(Z′)), CH(S—R^(Z)), C═O or CH(R^(Z)), whereR^(Z) is a C₁-C₆ aliphatic group or a carbocyclic or heterocyclic groupand R^(Z′) is H a C₁-C₆ aliphatic group.
 7. A compound having theFormula I-C:

wherein: R¹ is a carbocyclic group; R² is an aliphatic group, acarbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group,or a heterocyclic-aliphatic group; W is N; R^(2′) is H or a C₁-C₆ alkylgroup or R² and R^(2′) taken together with the atom W to which they areattached form an unsubstituted or substituted carbocyclic orheterocyclic ring; X is

R^(x) is H or one or more substituents independently selected fromalkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy,alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy,carboxyl, carbamoyl, formyl, alkylamino, dialkylamino,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl,alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy,alkylsulfonylamino, mercapto, and alkylthio; R⁸ and R^(8′) are eachindependently H, halo or a C₁-C₄ aliphatic group; Z is CF₂, CH(OH),CH(O—R^(Z)) or CH(R^(Z)), where R^(Z) is a C₁-C₆ aliphatic group or acarbocyclic or heterocyclic group; R³ is H or a C₁-C₆ aliphatic group;R⁴ and R⁵ are independently selected from H, halo, a C₁-C₆ aliphaticgroup or a group having the formula C(O)R^(4′), wherein R^(4′) is analiphatic, carbocyclic or heterocyclic group; R⁶ and R⁷ areindependently selected from H, halo or a C₁-C₆ aliphatic group; whereany of said aliphatic groups are saturated, partially saturated or fullyunsaturated and unsubstituted or substituted by one or more suitablesubstituents; and where any of said carbocyclic or heterocyclic groupsare unsubstituted or substituted by one or more suitable substituents;saturated, partially unsaturated or fully unsaturated; mono-, bi- ortri-cyclic; or a prodrug, pharmaceutically acceptable salt or solvatethereof.
 8. A compound having the Formula I-C:

wherein: R¹ is a carbocyclic group; R² is an aliphatic group, acarbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group,or a heterocyclic-aliphatic group; W is N; R^(2′) is H or a C₁-C₆ alkylgroup; X is

wherein R^(x) is H dialkylaminocarbonyl, alkylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl,alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy,alkylsulfonylamino, mercapto, or alkylthio; Z is CF₂, CH(OH) or C(═O);R³, R⁴ and R⁵ are each H; and R⁶ and R⁷ are each methyl; or a prodrug,pharmaceutically acceptable salt, or pharmaceutically acceptable solvatethereof.
 9. The compound, prodrug, salt, or solvate according to claim8, wherein: R¹ is an aryl group; R² is an alkyl, alkenyl, or alkynylgroup, an arylalkyl group; a heteroarylalkyl group, an indanyl group, achromanyl group, a tetrahydronaphthalene group, an aliphatic group, acarbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group,or a heterocyclic-aliphatic group; R^(2′) is H; wherein the alkyl,alkenyl, alkynyl, arylalkyl, heteroarylalkyl, indanyl, chromanyl ortetrahydronaphthalene group is unsubstituted or substituted with one ormore substituents independently selected from alkyl, hydroxy, halo,haloalkyl, cyano, alkoxy and methylenedioxy.
 10. A compound of formulaI-C:

wherein: R¹ is a phenyl group, where the phenyl group is unsubstitutedor substituted by at least one substitutent selected from hydroxyl andmethyl; R² is an C₁-C₅ alkyl, C₁-C₆ alkenyl, or C₁-C₄ alkynyl group, abenzyl group; a furanylmethyl group, a thienylmehtyl group, an indanylgroup, a chromanyl group, a tetrahydronaphthalene group, or acyclohexenyl group, where the alkyl groups is unsubstituted orsubstituted with one or more halogen; and the phenyl group isunsubstituted or substituted with halogen, hydroxyl, methoxy,methylenedioxy or methyl; R^(2′) is H; X is

wherein R^(x) is H; Z is CF₂; R³, R⁴ and R⁵ are each H; and R⁶ and R⁷are each methyl; or a prodrug, pharmaceutically acceptable salt, orpharmaceutically acceptable solvate thereof.
 11. The compound, prodrug,pharmaceutically acceptable salt, or pharmaceutically acceptable solvateaccording to claim 1, having the formula:

wherein R¹-R⁸, R^(2′), R^(8′), V, X, A, Z and W are as defined inclaim
 1. 12. The compound, prodrug, pharmaceutically acceptable salt, orpharmaceutically acceptable solvate according to claim 1, having theformula:

wherein R¹-R⁸, R^(2′), R^(8′), V, X, A, Z and W are as defined inclaim
 1. 13. The compound, prodrug, pharmaceutically acceptable salt, orpharmaceutically acceptable solvate according to claim 1, having theformula:

wherein R¹-R⁸, R^(2′), R^(8′), V, X, A, Z and W are as defined inclaim
 1. 14. A pharmaceutical composition comprising: a therapeuticallyeffective amount of at least one HIV agent selected from compounds,prodrugs, pharmaceutically acceptable salts, and pharmaceuticallyacceptable solvates defined in any one of claims 1, 2, 7 or 8; and apharmaceutically acceptable carrier, diluent, vehicle, or excipient. 15.The pharmaceutical composition according to claim 14, wherein thecomposition further comprises a therapeutically effective amount of atleast one HIV infection/AIDS treatment agent selected from the groupconsisting of HIV/AIDS antiviral agents, immunomodulators, andanti-infective agents.
 16. The pharmaceutical composition according toclaim 15, wherein the composition further comprises a therapeuticallyeffective amount of at least one antiviral agent selected from the groupconsisting of non-nucleoside HIV reverse transcriptase inhibitors andnucleoside HIV reverse transcriptase inhibitors.
 17. The pharmaceuticalcomposition according to claim 16, further comprising a therapeuticallyeffective amount of at least one HIV protease inhibitor.
 18. A compoundselected from:

or the prodrugs, and pharmaceutically acceptable salts and solvatesthereof.
 19. A compound having the formula:

wherein: R¹ is a carbocyclic; R² is an aliphatic group, a carbocyclicgroup, a carbocyclic-aliphatic group, a heterocyclic group, aheterocyclic-aliphatic group or N(R^(2a))R^(2b), wherein R^(2a) is analiphatic, carbocyclic or heterocyclic group, and R^(2b) is H or a C₁-C₆aliphatic group; W is N; R^(2′) is H or a C₁-C₆ aliphatic group or R²and R^(2′) taken together with the atom W to which they are attachedform an unsubstituted or substituted carbocyclic or heterocyclic ring; Xis

R^(x) is H or one or substituents independently selected from C₁-C₆alkyl, nitro, amino, cyano, halogen, C₁-C₆ haloalkyl, hydroxyl, C₁-C₆alkoxy, alkylenedioxy, C₁-C₆ alkylcarbonyl, C₁-C₆ alkyloxycarbonyl,C₁-C₆ alkylcarbonyloxy, carboxyl, carbamoyl, formyl, C₁-C₆ alkylamino,dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminothiocarbonyl, di-C₁-C₆-alkylaminothiocarbonyl, C₁-C₆alkylsulfonyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylcarbonylamino, C₁-C₆alkylthiocarbonylamino, C₁-C₆ alkylsulfonyloxy, C₁-C₆alkylsulfonylamino, mercapto, and C₁-C₆ alkylthio; R³ is H or a C₁-C₆aliphatic group; R⁴ and R⁵ are independently selected from H, halo, aC₁-C₆ aliphatic group or a group having the formula C(O)R^(4′), whereinR^(4′) is an aliphatic, carbocyclic or heterocyclic group; or R⁴ and R⁵,taken together with the atom to which they are bound, form anunsubstituted or substituted carbocyclic ring; R⁶ and R⁷ areindependently selected from H, halo or a C₁-C₆ aliphatic group; or R⁶and R⁷, taken together with the atom to which they are bound, form anunsubstituted or substituted carbocyclic or heterocyclic group; whereinany of said aliphatic groups are saturated, partially saturated or fullyunsaturated and unsubstituted or substituted by one or more suitablesubstituents; and wherein any of said carbocyclic or heterocyclic groupsare unsubstituted or substituted by one or more suitable substituents;saturated, partially unsaturated or fully unsaturated; or mono-, bi- ortri-cyclic; or a prodrug, pharmaceutically aceptable salt, orpharmaceutically acceptable solvate thereof.